Parallel, redundant circuit organization for homeostatic control of feeding behavior.

Neural circuits for essential natural behaviors are shaped by selective pressure to coordinate reliable execution of flexible goal-directed actions. However, the structural and functional organization of survival-oriented circuits is poorly understood due to exceptionally complex neuroanatomy. This is exemplified by AGRP neurons, which are a molecularly defined population that is sufficient to rapidly coordinate voracious food seeking and consumption behaviors. Here, we use cell-type-specific techniques for neural circuit manipulation and projection-specific anatomical analysis to examine the organization of this critical homeostatic circuit that regulates feeding. We show that AGRP neuronal circuits use a segregated, parallel, and redundant output configuration. AGRP neuron axon projections that target different brain regions originate from distinct subpopulations, several of which are sufficient to independently evoke feeding. The concerted anatomical and functional analysis of AGRP neuron projection populations reveals a constellation of core forebrain nodes, which are part of an extended circuit that mediates feeding behavior.

Geometrically programmed self-limited assembly of tubules using DNA origami colloids.

Self-assembly is one of the most promising strategies for making functional materials at the nanoscale, yet new design principles for making self-limiting architectures, rather than spatially unlimited periodic lattice structures, are needed. To address this challenge, we explore the tradeoffs between addressable assembly and self-closing assembly of a specific class of self-limiting structures: cylindrical tubules. We make triangular subunits using DNA origami that have specific, valence-limited interactions and designed binding angles, and we study their assembly into tubules that have a self-limited width that is much larger than the size of an individual subunit. In the simplest case, the tubules are assembled from a single component by geometrically programming the dihedral angles between neighboring subunits. We show that the tubules can reach many micrometers in length and that their average width can be prescribed through the dihedral angles. We find that there is a distribution in the width and the chirality of the tubules, which we rationalize by developing a model that considers the finite bending rigidity of the assembled structure as well as the mechanism of self-closure. Finally, we demonstrate that the distributions of tubules can be further sculpted by increasing the number of subunit species, thereby increasing the assembly complexity, and demonstrate that using two subunit species successfully reduces the number of available end states by half. These results help to shed light on the roles of assembly complexity and geometry in self-limited assembly and could be extended to other self-limiting architectures, such as shells, toroids, or triply periodic frameworks.

Phase Reentrances and Solid Deformations in Confined Colloidal Crystals.

A simple geometric constraint often leads to novel, complex crystalline phases distinct from the bulk. Using thin-film charge colloidal crystals, a model system with tunable interactions, we study the effects of geometric constraints. Through a combination of experiments and simulations, we systematically explore phase reentrances and solid deformation modes concerning geometrical confinement strength, identifying two distinct categories of phase reentrances below a characteristic layer number, N_{c}: one for bcc bulk-stable and another for fcc bulk-stable systems. We further verify that the dominant thermodynamic origin is the nonmonotonic dependence of solids' free energy on the degree of spatial confinement. Moreover, we discover transitions in solid deformation modes between interface-energy and bulk-energy dominance: below a specific layer number, N_{k}, geometric constraints generate unique soft deformation modes adaptive to confinement. These findings on the N-dependent thermodynamic and kinetic behaviors offer fresh insights into understanding and manipulating thin-film crystal structures.

Comparative effectiveness and functional outcome of C3 & C7 dome-hybrid open-door laminoplasty with traditional unilateral open-door laminoplasty for cervical spondylotic myelopathy.

OBJECTIVE: The C3 & C7 dome-hybrid open-door laminoplasty was proven to be an effective treatment for multi-levels cervical spondylotic myelopathy (CSM). However, its superiority over traditional unilateral open-door laminoplasty (UOLP) remains questionable, and no studies have compared the efficacy of this technique with traditional UOLP. This study aimed to compare the effectiveness of C3 & C7 dome-hybrid open-door laminoplasty with traditional UOLP in treating multi-levels CSM. METHODS: A retrospective study of multi-levels CSM with laminoplasty was performed, including 35 cases of traditional UOLP and 27 cases of C3 & C7 dome-hybrid open-door laminoplasty. Radiographic evaluation parameters and clinical outcomes were recorded to evaluate the surgical effectiveness. RESULTS: There was no significant difference in demographic baseline parameters. At the final follow-up, the C2-C7 Cobb angle of the modified group was significantly greater than that of the traditional group (p = 0.026). Meanwhile, the C2-C7 SVA of the modified group was significantly smaller than that of the traditional group (p = 0.009). Clinical outcomes such as VAS, NDI, and SF-12 scores, improved significantly in the modified group compared to the traditional group, while the JOA scores had no significant difference in both groups. There was no significant difference in the overall rate of complications between the two groups. CONCLUSION: Both techniques have satisfactory outcomes in treating multi-levels CSM. Comparing with traditional UOLP, C3 & C7 dome-hybrid open-door laminoplasty has a greater superiority in reducing postoperative neck pain and maintaining the cervical sagittal alignment. It is proven to be a feasible management for patients with multi-levels CSM.

Peripherin: A proposed biomarker of traumatic axonal injury triggered by mechanical force.

Traumatic axonal injury (TAI) is one of the most common pathological features of severe traumatic brain injury (TBI). Our previous study using proteomics suggested that peripherin (PRPH) should be a potential candidate as a biomarker for TAI diagnosis. This study is to further elucidate the role and association of PRPH with TAI. In the animal study, we performed immunohistochemistry, ELISA and morphological analysis to evaluate PRPH level and distribution following a severe impact. PRPH-positive regions were widely distributed in the axonal tract throughout the whole brain. Axonal injuries with PRPH inclusion were observed post-TBI. Besides, PRPH was significantly increased in both cerebral spinal fluid and plasma at the early phase post-TBI. Colocalization analysis based on microscopy revealed that PRPH represents an immunohistological biomarker in the neuropathological diagnosis of TAI. Brain samples from patients with TBI were included to further test whether PRPH is feasible in the real practice of neuropathology. Immunohistochemistry of PRPH, NFH, APP and NFL on human brain tissues further confirmed PRPH as an immunohistological biomarker that could be applied in practice. Collectively, we conclude that PRPH mirrors the cytoskeleton injury of axons and could represent a neuropathological biomarker for TAI.

A simple method to alter the binding specificity of DNA-coated colloids that crystallize.

DNA-coated colloids can crystallize into a multitude of lattices, ranging from face-centered cubic to diamond, opening avenues to producing structures with useful photonic properties. The potential design space of DNA-coated colloids is large, but its exploration is hampered by a reliance on chemically modified DNA that is slow and expensive to commercially synthesize. Here we introduce a method to controllably tailor the sequences of DNA-coated particles by covalently appending new sequence domains onto the DNA grafted to colloidal particles. The tailored particles crystallize as readily and at the same temperature as those produced via direct chemical synthesis, making them suitable for self-assembly. Moreover, we show that particles coated with a single sequence can be converted into a variety of building blocks with differing specificities by appending different DNA sequences to them. This method will make it practical to identify optimal and complex particle sequence designs and paves the way to programming the assembly kinetics of DNA-coated colloids.

Two-step crystallization and solid-solid transitions in binary colloidal mixtures.

Crystallization is fundamental to materials science and is central to a variety of applications, ranging from the fabrication of silicon wafers for microelectronics to the determination of protein structures. The basic picture is that a crystal nucleates from a homogeneous fluid by a spontaneous fluctuation that kicks the system over a single free-energy barrier. However, it is becoming apparent that nucleation is often more complicated than this simple picture and, instead, can proceed via multiple transformations of metastable structures along the pathway to the thermodynamic minimum. In this article, we observe, characterize, and model crystallization pathways using DNA-coated colloids. We use optical microscopy to investigate the crystallization of a binary colloidal mixture with single-particle resolution. We observe classical one-step pathways and nonclassical two-step pathways that proceed via a solid-solid transformation of a crystal intermediate. We also use enhanced sampling to compute the free-energy landscapes corresponding to our experiments and show that both one- and two-step pathways are driven by thermodynamics alone. Specifically, the two-step solid-solid transition is governed by a competition between two different crystal phases with free energies that depend on the crystal size. These results extend our understanding of available pathways to crystallization, by showing that size-dependent thermodynamic forces can produce pathways with multiple crystal phases that interconvert without free-energy barriers and could provide approaches to controlling the self-assembly of materials made from colloids.

Polymorphic self-assembly of helical tubules is kinetically controlled.

In contrast to most self-assembling synthetic materials, which undergo unbounded growth, many biological self-assembly processes are self-limited. That is, the assembled structures have one or more finite dimensions that are much larger than the size scale of the individual monomers. In many such cases, the finite dimension is selected by a preferred curvature of the monomers, which leads to self-closure of the assembly. In this article, we study an example class of self-closing assemblies: cylindrical tubules that assemble from triangular monomers. By combining kinetic Monte Carlo simulations, free energy calculations, and simple theoretical models, we show that a range of programmable size scales can be targeted by controlling the intricate balance between the preferred curvature of the monomers and their interaction strengths. However, their assembly is kinetically controlled-the tubule morphology is essentially fixed shortly after closure, resulting in a distribution of tubule widths that is significantly broader than the equilibrium distribution. We develop a simple kinetic model based on this observation and the underlying free-energy landscape of assembling tubules that quantitatively describes the distributions. Our results are consistent with recent experimental observations of tubule assembly from triangular DNA origami monomers. The modeling framework elucidates design principles for assembling self-limited structures from synthetic components, such as artificial microtubules that have a desired width and chirality.

Neurons for hunger and thirst transmit a negative-valence teaching signal.

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

Bone mesenchymal stem cell-conditioned medium attenuates the effect of oxidative stress injury on NSCs by inhibiting the Notch1 signaling pathway.

Numerous studies have demonstrated the therapeutic effect of bone mesenchymal stem cells on spinal cord injury (SCI), especially on neural stem cells (NSCs). However, the predominant mechanisms of bone mesenchymal stem cells (BMSCs) are unclear. Recently, some researchers have found that paracrine signaling plays a key role in the therapeutic capacity of BMSCs and emphasized that the protective effect of BMSCs may be due to paracrine factors. In this study, we aimed to investigate the potential mechanisms of BMSCs to protect NSCs. NSCs were identified by immunocytochemistry. The oxidative stress environment was simulated by H2 O2 (50, 100, 200 µM) for 2 h. The apoptotic rate of the NSCs was detected via flow cytometry. Lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) activity were evaluated via corresponding assay kits. Western blot was used to detect the expressions of Notch1, HES1, caspase-3, cleave caspase-3, Bax, and Bcl-2. We found that H2 O2 could significantly induce the apoptosis of NSCs, increase LDH, MDA levels, and decrease SOD activity by activating the Notch1 signaling pathway. DAPT (the specific blocker of Notch1) and BMSC-conditioned medium (BMSC-CM) could significantly prevent the apoptotic effect and oxidative stress injury on NSCs that were treated with H2 O2 . We also revealed that BMSC-CM could decrease the expression of Notch1, Hes1, cleave caspase-3, Bax, and increases the expression of Bcl-2 in NSCs, which was induced by H2 O2 . These results have revealed that BMSC-CM can neutralize the effect against oxidative stress injury on the apoptosis of NSCs by inhibiting the Notch1 signaling pathway.

Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway.

As a major cause of renal failure, transient renal ischemia and reperfusion induce both acute kidney injury and late fibrosis, which are the common pathological manifestations of end-stage renal disease. Curcumin is a biologically active polyphenolic compound found in turmeric. Increasing evidence has demonstrated that curcumin has a protective action against renal fibrosis, whereas mechanisms underlying the anti-fibrosis role of curcumin remain poorly defined. Here, we found that APPL1, an important intracellular binding partner for AdipoR, was involved in the pathogenesis of acute injury or fibrosis and was significantly upregulated by curcumin in a mouse model of ischemia reperfusion-induced late kidney fibrosis. Moreover, Akt signaling was the specific signaling pathway identified downstream of APPL1 in the pathogenesis of fibrosis. Our in vitro experiment demonstrated that curcumin alleviates ischemia reperfusion-induced late kidney fibrosis via the APPL1/Akt pathway. These data are helpful for understanding the anti-fibrosis mechanism of curcumin in the pathogenesis of AKI-induced late fibrosis.

(2R,3R)Dihydromyricetin inhibits osteoclastogenesis and bone loss through scavenging LPS-induced oxidative stress and NF-κB and MAPKs pathways activating.

Osteolysis is a serious complication of several chronic inflammatory diseases and is closely associated with a local chronic inflammatory reaction with a variety of causes. However, similarities exist in the mechanisms of their pathological processes. Inflammatory factors and oxidative stress-induced nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways play a center role in bone erosion. Dihydromyricetin (DMY) is a natural compound with anti-inflammatory and antioxidative effect, which are commonly used in chronic pharyngitis and alcohol use disorders. In the current study, we identified that DMY attenuated lipopolysaccharide (LPS)-induced oxidative stress through inhibiting the production of reactive oxygen species (ROS) and nitric oxide (NO), downregulated COX-2 and iNOS, and promoted the activity of the antioxidative system by activating superoxide dismutase (SOD) and Nrf2/HO-1 pathway. To further investigate the underlying mechanism, we found that DMY inhibits osteoclast (OC) differentiation and bone resorption activity through blocking the RANKL-induced activation of the NF-κB and MAPKs signaling pathways and then downregulated c-Fos and NFATc1, which is essential for OC differentiation. Furthermore, DMY inhibited LPS-induced osteolysis in vivo. Collectively, these results indicate that DMY might be a promising prophylactic antiosteoclastic/resorptive agent in preventing or treating bone lysis diseases.

Robot-assisted and conventional freehand pedicle screw placement: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Several studies have revealed that robot-assisted technique might improve the pedicle screw insertion accuracy, but owing to the limited sample sizes in the individual study reported up to now, whether or not robot-assisted technique is superior to conventional freehand technique is indefinite. Thus, we performed this systematic review and meta-analysis based on randomized controlled trials to assess which approach is better. METHODS: Electronic databases including PubMed, EMBASE, CENTRAL, ISI Web of Science, CNKI and WanFang were systematically searched to identify potentially eligible articles. Main endpoints containing the accuracy of pedicle screw implantation and proximal facet joint violation were evaluated as risk ratio (RR) and the associated 95% confidence intervals (95% CIs), while radiation exposure and surgical duration were presented as mean difference (MD) or standard mean difference (SMD). Meta-analyses were performed using RevMan 5.3 software. RESULTS: Six studies involving 158 patients (688 pedicle screws) in robot-assisted group and 148 patients (672 pedicle screws) in freehand group were identified matching our study. The Grade A accuracy rate in robot-assisted group was superior to freehand group (RR 1.03, 95% CI 1.00, 1.06; P = 0.04), but the Grade A + B accuracy rate did not differ between the two groups (RR 1.01, 95% CI 0.99, 1.02; P = 0.29). With regard to proximal facet joint violation, the combined results suggested that robot-assisted group was associated with significantly fewer proximal facet joint violation than freehand group (RR 0.07, 95% CI 0.01, 0.55; P = 0.01). As was the radiation exposure, our findings suggested that robot-assisted technique could significantly reduce the intraoperative radiation time (MD - 12.38, 95% CI - 17.95, - 6.80; P < 0.0001) and radiation dosage (SMD - 0.64, 95% CI - 0.85, - 0.43; P < 0.00001). But the overall surgical duration was longer in robot-assisted group than conventional freehand group (MD 20.53, 95% CI 5.17, 35.90; P = 0.009). CONCLUSIONS: The robot-assisted technique was associated with equivalent accuracy rate of pedicle screw implantation, fewer proximal facet joint violation, less intraoperative radiation exposure but longer surgical duration than freehand technique. Powerful evidence relies on more randomized controlled trials with high quality and larger sample size in the future.

Association between polymorphisms in vitamin D receptor gene and adolescent idiopathic scoliosis: a meta-analysis.

PURPOSE: This meta-analysis was performed to clarify whether the two single nucleotide polymorphisms (ApaI and BsmI) in vitamin D receptor (VDR) gene conferred susceptibility to adolescent idiopathic scoliosis (AIS). METHODS: A comprehensive literature search in five online databases (PubMed, EMBASE, ISI Web of Science, CNKI, and Wanfang) was performed to identify studies that analyzed the association between VDR gene polymorphisms and risk of AIS. Observational studies met the predetermined inclusion criteria were selected for meta-analysis. The most appropriate genetic model was identified using a genetic model-free approach. Meta-analysis was performed using RevMan 5.3 software. RESULTS: Five eligible studies were included in this meta-analysis, which involved a total of 717 cases and 554 controls. A statistically significant association was observed between BsmI polymorphism and AIS (OR 1.90, 95% CI 1.32, 2.62). In subgroup analysis by ethnicity, the association between BsmI polymorphism and AIS was significant in Asians (OR 2.06, 95% CI 1.56, 2.73) but not in Caucasians (OR 0.70, 95% CI 0.23, 2.19). However, the ApaI polymorphism was not associated with AIS. Moreover, no evidence of association between BMD and the two VDR gene polymorphisms was detected. CONCLUSIONS: Meta-analysis of existing data suggested that BsmI was associated with increased risk of AIS in Asian populations. Nevertheless, further studies with rigorous design and more ethnic groups are encouraged to validate our findings. These slides can be retrieved under Electronic Supplementary Material.

Factors affecting Pap smear uptake in a maternity hospital: A descriptive cross-sectional study.

AIM: To understand factors that influence women's decisions to go for Pap smears. BACKGROUND: Globally, cervical cancer is the fourth most common cancer among women. In Singapore, cervical cancer is on the rise and has been found to be the eighth highest cause of death among women. Research has shown that regular screening for cervical cancer with Pap smear reduces cervical cancer-related mortality. However, Pap smear awareness is still limited and its uptake in Singapore is highly opportunistic, requiring the need for a deeper understanding of the factors that influence Pap smear uptake among women in Singapore. DESIGN: A descriptive cross-sectional study design was used. METHODS: Convenience sampling was used to recruit 350 participants (postnatal women of at least 21 years old) from a local maternity hospital. Data were collected using validated questionnaires. Logistic regression was used to analyse the data. RESULTS: Demographic factors, such as age, ethnicity and religion, as well as women's beliefs about the effectiveness of Pap smear in detecting cervical cancer, the desire to discover health problems early and considering Pap smear to be painful, were found to be factors significantly influencing Pap smear uptake. Healthcare professionals need to be mindful of these factors to address women's needs to encourage women to go for Pap smears. CONCLUSION: Various factors were found to influence Pap smear uptake. Future interventions can take these factors into account for increasing Pap smear awareness.

Conjugated linoleic acid prevents age-induced bone loss in mice by regulating both osteoblastogenesis and adipogenesis.

Osteoporosis (OP) can increase the risk of bone fracture and other complications, which is a major clinical problem. Previous researches have revealed that conjugated linoleic acid (CLA) can promote the bone formation. But the mechanisms are not clear. Thus, we tested the hypothesis that CLA acts on bone formation might be via mTOR Complex1 (mTORC 1) pathway by in vitro and vivo assays. We studied the effect of CLA mix on MC3T3-E1 pre-osteoblasts differentiation into osteoblasts, and bone formation under osteoporotic conditions. At the same time, 3T3-L1 pre-adipocyte with the same CLA mix concentration gradient for 8 days with adipogenic differentiation medium. We found that Alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) expressions of pre-osteoblasts were up-regulated. Moreover in presence of CLA, peroxisome proliferators-activated receptor γ(PPARγ) and CCAAT/enhancer-binding protein (C/EBPα) were down-regulated. Osteoporosis mice bone parameters in the distal femoral meraphysis were significantly increased compared with placebo mice. Furthermore, the phosphor-S6 (P-S6) was suppressed and phosphor-AKT (P-AKT) was up-regulated. Consistently, CLA can stimulate differentiation of osteoblasts and inhibited pre-adipocytes differentiated into adipocytes via AKT/mTORC1 signal pathway. Overall CLA thus be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and obesity.

Association between IGF1 gene single nucleotide polymorphism (rs5742612) and adolescent idiopathic scoliosis: a meta-analysis.

PURPOSE: Insulin-like growth factor 1 (IGF1) gene single nucleotide polymorphism (rs5742612) has been associated with adolescent idiopathic scoliosis (AIS) in several studies with limited sample size and inconsistent outcomes. So we perform this meta-analysis to assess the precise association between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS. METHODS: We systematically searched Pubmed, Embase, Web of Science and Cochrane Library up to January 19, 2016 to obtain relevant studies using our research strategy. Four articles all belonging to case-control studies were included in our meta-analysis. RESULTS: A total of four studies containing 763 cases and 559 controls satisfied the inclusion criteria after judgment by two reviewers. No significant associations were detected between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS (T vs. C, OR = 1.10, 95 % CI 0.91-1.34, p = 0.32; TT vs. CC: OR = 1.28, 95 % CI 0.82-2.02, p = 0.28; TC vs. CC: OR = 1.29, 95 % CI 0.82-2.06, p = 0.27; TT/TC vs. CC: OR = 1.28, 95 % CI 0.83-1.98, p = 0.27; TT vs. TC/CC: OR = 1.06, 95 % CI 0.82-1.36, p = 0.66). CONCLUSIONS: IGF1 gene single nucleotide polymorphism (rs5742612) is not significant associated with susceptibility to AIS in either Asian or Caucasian populations. However, IGF1 gene rs5742612 may be associated with severity of AIS. Further studies with larger sample size and different population groups involving the relationship are required to confirm the potential association.

Mutation analysis for detection of drug resistance in mycobacterium tuberculosis isolates from Khyber Pakhtunkhwa, Pakistan.

OBJECTIVE: To examine the frequency and distribution of mutations in the 'hot spot regions' of drug-resistant genes. METHODS: The study was conducted at Provincial Tuberculosis Reference Laboratory, Peshawar, Pakistan, from April 2015 to March 2016, and comprised sputum samples. Isolates were tested for drug susceptibility and resistant isolates were investigated for mutations analysis in the 'hot spot regions' of rpoB, rpsL, embB, pncA, gyrA and gyrB genes. RESULTS: Of the 163 isolates, 47(28.8%) isolates were resistant to streptomycin, 56(34.36%) to rifampicin, 31(19%) to ethambutol, 16(9.82%) to pyrazinamide and 59(36.2%) isolates were resistant to ofloxacin. Resistant isolates were randomly selected for mutation analysis. Moreover, 14(25%) rifampicin-resistant isolates were analyed for mutation in rpoB gene. Ser450Leu, Asp435Gly, Ser450Gln, Gly455Asp and Pro454His mutations were detected in the selected isolates. Furthermore, 16(34%) streptomycin-resistant isolates were analysed for mutation in rpsL gene. Lys43Arg, Lys88Arg and Lys111Ile mutations were detected in rpsL gene of 6(37.5%) isolates. Besides, 16(51.6%) ethambutol-resistant isolates were analysed for mutations in embB mutation; Ala281val, Met306Leu and Met306Val mutations were detected in 10(10(62.5%) isolates. Also, 8(50%) pyrazinamide-resistant isolates were analysed for mutation in pncA gene. CONCLUSIONS: Some novel mutations were found in rpoB, rpsL and pncA genes.

CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling.

Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36(-/-) mice was decreased. CD36(-/-) mice also showed aggravated neurologic deficits and increased TNF-α and IL-1ß expression levels. The phagocytic capacity of CD36(-/-) microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4(-/-) and MyD88(-/-) mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1ß significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.

Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3.

Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1ß levels were markedly decreased, whereas IFN-ß levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1ß in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.