Soil-root interface hydraulic conductance determines responses of photosynthesis to drought in rice and wheat.

Rice (Oryza sativa) production consumes a huge amount of fresh water, and improvement of drought tolerance in rice is important to conserve water resources and minimize yield loss under drought. However, processes to improve drought tolerance in rice have not been fully explored, and a comparative study between rice and wheat (Triticum aestivum) is an effective method to understand the mechanisms determining drought tolerance capacity. In the present study, we applied short-term drought stress to Shanyou 63 rice and Yannong 19 wheat to create a range of water potentials and investigated the responses of gas exchange, plant hydraulic conductance, and root morphological and anatomical traits to soil drought. We found that photosynthesis in rice was more sensitive to drought stress than that in wheat, which was related to differences in the decline of stomatal conductance and plant hydraulic conductance (Kplant). The decline of Kplant under drought was mainly driven by the decrease of soil-root interface hydraulic conductance (Ki) because Ki was more sensitive to drought than root and shoot hydraulic conductance and the soil-root interface contributed to >40% of whole-plant hydraulic resistance in both crops. Root shrinkage in response to drought was more severe in rice than that in wheat, which explains the larger depression of Ki and Kplant under drought stress in rice. We concluded that the decline of Ki drives the depression of Kplant and photosynthesis in both crops, and the plasticity of root morphology and anatomy is important in determining drought tolerance capacity.

Aspartoacylase promotes the process of tumour development and is associated with immune infiltrates in gastric cancer.

BACKGROUND: Aspartoacylase (ASPA) is a gene that plays an important role in the metabolic reprogramming of cancer. However, the clinical relevance of ASPA in gastric cancer (GC) has not been demonstrated. METHODS: The link between ASPA and the clinical features of GC was determined using two public genomic databases. The multivariate Cox proportional hazard model and generalised linear regression model were applied to examine whether the ASPA level is associated with the prognosis and other pathological factors. In addition, the role of specific genes in the infiltration of immune cells in the setting of GC was investigated using a further immunological database. The expression level of various proteins was detected using a western blotting assay. Transwell and methyl thiazolyl tetrazolium tests were applied for the detection of cellular invasion and proliferation, with small hairpin ribonucleic acid used to knockdown ASPA. RESULTS: According to the multivariate Cox regression results, the down-regulated ASPA expression is a distinct prognostic factor. Furthermore, ASPA has significant positive correlations with the infiltration of immune cells in GC lesions. Compared to the non-cancer tissues, the GC tissues had a significantly lower level of ASPA expression (p < 0.05). Using knockdown and overexpression techniques, it was demonstrated that ASPA affects the capacity of cell lines for GC to both proliferate and invade. CONCLUSION: Overall, ASPA could promote the occurrence and development of GC and presents a promising predictive biomarker for the disease since it is favourably connected with immune infiltrates and negatively correlated with prognosis.

Advances in Oral Drug Delivery Systems: Challenges and Opportunities.

The oral route is the most preferred route for systemic and local drug delivery. However, the oral drug delivery system faces the harsh physiological and physicochemical environment of the gastrointestinal tract, which limits the bioavailability and targeted design of oral drug delivery system. Innovative pharmaceutical approaches including nanoparticulate formulations, biomimetic drug formulations, and microfabricated devices have been explored to optimize drug targeting and bioavailability. In this review, the anatomical factors, biochemical factors, and physiology factors that influence delivering drug via oral route are discussed and recent advance in conventional and novel oral drug delivery approaches for improving drug bioavailability and targeting ability are highlighted. We also address the challenges and opportunities of oral drug delivery systems in future.

Comprehensive genomic profiling of colorectal cancer patients reveals differences in mutational landscapes among clinical and pathological subgroups.

With the widespread of colonoscopy, colorectal cancer remains to be one of the most detrimental types of cancer. Though there were multiple studies investigating the genomic landscape of colorectal cancer, a comprehensive analysis uncovering the differences between various types of colorectal cancer is still lacking. In our study, we performed genomic analysis on 133 patients with colorectal cancer. Mutated FAT1 and PKHD1 and altered Hippo pathway genes were found to be enriched in early-onset colorectal cancer. APOBEC signature was prevalent in microsatellite stable (MSS) patients and was related to lymph node metastasis. ZNF217 mutations were significantly associated with early-stage colorectal cancer. In all, this study represents a comprehensive genomic analysis uncovering potential molecular mechanisms underneath different subgroups of colorectal cancer thus providing new targets for precision treatment development.

Identification of Prognostic LncRNAs Subtypes Predicts Prognosis and Immune Microenvironment for Glioma.

Glioma is the most commonly occurring primary neuroepithelial neoplasm. Long noncoding RNAs (lncRNAs) are emerging as pivotal modulators of gene expression in the immune system and play critical roles in the growth, progression, and immune response of carcinomas. In this study, we performed univariate Cox regression analysis on survival data from TCGA and identified 20 prognostic lncRNAs. Moreover, we revealed that these prognosis-related lncRNAs (PRLnc) were dysregulated in glioma. Furthermore, we constructed a signature based on the expression levels of these prognosis-related lncRNAs based on 13 prognostic lncRNAs, including AGAP2-AS1, CYTOR, MIR155HG, LINC00634, HOTAIRM1, SNHG18, LINC01841, LINC01842, LINC01426, MIR9-3HG, TMEM220-AS1, LINC00641, LINC01270, and LINC01503. The Kaplan-Meier curves show that high-risk patients had a shorter survival time. Finally, the glioma samples were classified into 2 subgroups based on the median expression of prognosis-related lncRNAs in each sample. In summary, these findings suggest that PRLnc is associated with tumor-infiltrating immune cells in glioma and that subtype 2 patients may respond more positively to immunotherapy.

Senkyunolide H inhibits activation of microglia and attenuates lipopolysaccharide-mediated neuroinflammation and oxidative stress in BV2 microglia cells via regulating ERK and NF-κB pathway.

Neuropathic pain is one of the common surgical diseases, which leads to abnormal chronic pain and pain hypersensitivity reaction. Microglia are important glial cells in the spinal cord, which are conducive to sensitization and maintenance of chronic pain. Recently, Senkyunolide H (SNH) has been reported to play an anti-inflammatory and antioxidant role. However, the mechanisms by which SNH improves neuropathic pain symptoms remain unknown. This study aimed to evaluate and identify the role of SNH in lipopolysaccharide (LPS)-mediated neuroinflammation and oxidative stress in BV2. Western blot and immunostaining assays revealed that SNH treatment attenuated LPS-mediated activation of BV2 in a dose-dependent manner. Flow cytometry further verified that BV2 microglial cells gradually shifted from an M1 (pro-inflammatory) phenotype to an M2 (anti-inflammatory) phenotype after SNH administration. Furthermore, quantitative real-time polymerase chain reaction and ELISA assays demonstrated that SNH treatment attenuated LPS-mediated neuroinflammation and oxidative stress in BV2 microglial cells. Lastly, western blot assays suggested that SHN could inactivate the ERK and NF-κB signaling pathways. Altogether, our findings have demonstrated that SNH could reverse LPS-mediated activation of microglia, LPS-mediated neuroinflammation and oxidative stress in BV2 via regulating the ERK and NF-κB pathways.

Immunodeficiencies Push Readmissions in Malignant Tumor Patients: A Retrospective Cohort Study Based on the Nationwide Readmission Database.

BACKGROUND: Immunodeficiency diseases (IDDs) are associated with an increased proportion of cancer-related morbidity. However, the relationship between IDDs and malignancy readmissions has not been well described. Understanding this relationship could help us to develop a more reasonable discharge plan in the special tumor population. METHODS: Using the Nationwide Readmissions Database, we established a retrospective cohort study that included patients with the 16 most common malignancies, and we defined two groups: non-immunodeficiency diseases (NOIDDs) and IDDs. RESULTS: To identify whether the presence or absence of IDDs was associated with readmission, we identified 603,831 patients with malignancies at their time of readmission in which 0.8% had IDDs and in which readmission occurred in 47.3%. Compared with NOIDDs, patients with IDDs had a higher risk of 30-day (hazard ratio (HR) of 1.32; 95% CI of 1.25-1.40), 90-day (HR of 1.27; 95% CI of 1.21-1.34) and 180-day readmission (HR of 1.28; 95% CI of 1.22-1.35). More than one third (37.9%) of patients with IDDs had readmissions that occurred within 30 days and most (82.4%) of them were UPRs. An IDD was an independent risk factor for readmission in patients with colorectal cancer (HR of 1.32; 95% CI of 1.01-1.72), lung cancer (HR of 1.23; 95% CI of 1.02-1.48), non-Hodgkin's lymphoma (NHL) (HR of 1.16; 95% CI of 1.04-1.28), prostate cancer (HR of 1.45; 95% CI of 1.07-1.96) or stomach cancer (HR of 2.34; 95% CI of 1.33-4.14). Anemia (44.2%), bacterial infections (28.6%) and pneumonia (13.9%) were the 30-day UPR causes in these populations. (4) Conclusions: IDDs were independently associated with higher readmission risks for some malignant tumors. Strategies should be considered to prevent the causes of readmission as a post discharge plan.

Association of CSMD1 with Tumor Mutation Burden and Other Clinical Outcomes in Gastric Cancer.

BACKGROUND: Immunotherapy is considered as a powerful and promising clinical approach for the treatment of gastric cancer (GC). However, it is still challenging to precisely screen patients who potentially benefit from immune checkpoint therapy (ICT). Identification of potential biomarkers for selecting patients sensitive to immunotherapy was urgently needed. METHODS: Public sequence data and corresponding clinical data were used to explore the potential biomarkers for immunotherapy. RESULTS: We found that CSMD1 is the most frequently mutated gene and its mutation is highly correlated with prognosis in gastric cancer patients. Interestingly, patients with mutated CSMD1 exhibit a high mutation burden and upregulated PDL1 expression. The ratio of microsatellite instability (MSI) in the CSMD1 mutation cohort was higher than that in the cohort without CSMD1 mutation. Furthermore, patients with CSMD1 mutation have been found to possess a higher number of activated CD4+ T cells and neoantigens. CONCLUSION: CSMD1 mutation may act as a novel biomarker for assessing the survival and immune therapy response in patients with gastric cancer.

Rs41291957 polymorphism in the promoter region of microRNA­143 serves as a prognostic biomarker for patients with intracranial hemorrhage.

The present study aimed to investigate the function of the single nucleotide polymorphism (SNP) rs41291957 in the prognosis of intracerebral hemorrhage (ICH). In addition, the molecular mechanisms underlying the role of microRNA (miR)­143, Toll­like receptor 2 (TLR2) and interleukin­16 (IL­16) were studied in patients with ICH that carried different alleles in the locus of the rs41291957 SNP. Kaplan­Meier survival curves were calculated for 182 patients with ICH, genotyped as CC, presenting a cytosine in both chromosome, CT, presenting both variants, and TT, presents a thymine in both chromosomes. In addition, the possible regulatory relationships between miR­143 and TLR2/IL­16 were studied using computational analysis, luciferase assays and western blot assay. In addition, the inflammatory profiles of cerebrospinal fluid (CSF) and serum samples collected from the subjects were compared. The patients genotyped as TT presented the lowest survival rate, while patients genotyped as CC presented the highest survival rate. TLR2 mRNA was identified as a potential target of miR­143, while IL­16 showed no direct interaction with miR­143. The above regulatory relationships were further investigated using cells transfected with miR­143 precursor or TLR2 small interfering RNA. In addition, the expression levels of inflammatory factors, such as tumor necrosis factor α, interferon, IL­6, IL­10 and NF­L­6, were highest in the CSF/serum samples collected from patients genotyped as TT and lowest in patients genotyped as CC. By contrast, the expression levels of miR­143 showed an opposite trend in the expression of the above inflammatory factors. The rs41291957 SNP, located in the promoter region of miR­143, reduced the expression of miR­143 and upregulated the expression of the pro­inflammatory factor TLR2, eventually leading to a poorer prognosis in patients with ICH.

Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via the ABCA1 transmembrane transport system in APP/PS1 double transgenic mice.

The disorder of lipid metabolism, especially cholesterol metabolism, can promote Alzheimer's Disease. Curcumin can ameliorate lipid metabolic disorder in the brain of Alzheimer's Disease patients, while the mechanism is not clear. APP/PS1 (APPswe/PSEN1dE9) double transgenic mice were divided into dementia, low-dose, and high-dose groups and then fed for six months with different dietary concentrations of curcumin. Morris water maze was used to evaluate the transgenic mice's special cognitive and memory ability in each group. In contrast, the cholesterol oxidase-colorimetric method was used to measure total serum cholesterol and high-density lipoprotein levels. Immunohistochemistry was used to evaluate the expression of liver X receptor-ß, ATP binding cassette A1 and apolipoprotein A1 of the hippocampus and Aß42 in the brains of transgenic mice. The mRNA and protein expression levels of liver X receptor-ß, retinoid X receptor-α and ATP binding cassette A1 were evaluated using qRT-PCR and Western blotting, respectively. Curcumin improved the special cognitive and memory ability of transgenic Alzheimer's Disease Mice. The total serum cholesterol decreased in Alzheimer's Disease mice fed the curcumin diet, while the high-density lipoprotein increased. The curcumin diet was associated with reduced expression of Aß and increased expression of liver X receptor-ß, ATP binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus. The mRNA and protein levels of retinoid X receptor-α, liver X receptor-ß, and ATP binding cassette A1 were higher in the brains of Alzheimer's Disease mice fed the curcumin diet. Our results point to the mechanism by which curcumin improves lipid metabolic disorders in Alzheimer's Disease via the ATP binding cassette A1 transmembrane transport system.

Correlation Between SNPs at the 3'UTR of the FGF2 Gene and Their Interaction with Environmental Factors in Han Chinese Diabetic Peripheral Neuropathy Patients.

FGF2 is a neurotrophic factor that can act as a key regulatory molecule of neuroprotection, neurogenesis, and angiogenesis in various injuries. To explore the genetic background of the FGF2 gene on DPN development, this study analyzed the correlation between SNPs in the 3'UTR of the FGF2 gene and their interaction with environmental factors in DPN patients of Han Chinese nationality. Sanger sequencing was used to analyze the FGF2 genotypes at the rs1048201, rs3804158, rs41348645, rs6854081, rs3747676, rs7683093, rs1476215, and rs1476217 loci in 150 DPN patients, 150 NDPN patients, and 150 healthy control patients. Plasma FGF2 levels were measured in all subjects by using ELISAs. Subjects carrying the T allele at the rs1048201 locus in the FGF2 gene had a significantly lower risk of developing DPN compared with subjects carrying the C allele (OR = 0.43, 95% CI = 0.33-0.56, p < 0.01). Subjects with the G genotype at the rs6854081 locus had an exceptionally higher risk of developing DPN than subjects with the T allele (OR = 1.66, 95% CI = 1.39-1.89, p < 0.01). Individuals harboring the G allele at the rs7683093 locus had a markedly higher risk of DPN than patients with the C allele (OR = 1.63, 95% CI = 1.36-1.87, p < 0.01). Finally, individuals having the A genotype at the rs1476215 locus had a significantly higher risk of DPN than individuals carrying the T allele (OR = 1.82, 95% CI = 1.53-2.02, p < 0.01). There was an interaction between age and alcohol consumption and the SNP rs7683093. SNPs at rs1048201, rs6854081, rs7683093, and rs1476215 in the FGF2 3'UTR were strongly associated with plasma levels of FGF2 (p < 0.05). SNPs at the rs1048201, rs6854081, rs7683093, and rs1476215 loci in the FGF2 gene were significantly associated with the risk of DPN. A possible mechanism is that these SNPs affect the expression level of FGF2 by interrupting the binding of microRNAs to target sites in the 3'UTR.

Prevention of Obesity Related Diseases through Laminarin-induced targeted delivery of Bindarit.

Rationale: The developement of oral targeted therapeutics for obesity and obesity-related diseases is challenging, as these diseases involve multiple lesions distributed throughout the whole body. Herein, we report a successful stragety for targeted oral delivery of bindarit to multiple obesity-related lesions including inflamed adipose tissue, fatty liver and atherosclerotic plaques. Methods: The computer simulation from atomstic to mesoscale was first applied for designing bindarit-loaded nanoparticles (pBIN) and laminarin-modified bindarit-loaded nanoparticles (LApBIN). Then pBIN were suceesfully prepared using a dialysis procedure, and LApBIN were prepared though the interaction bewtween laminarin and pBIN. The physiochemical properties, in vitro and in vivo pharmacokinetics, oral targeting capability and in vivo efficacy of LApBIN in various obesity-related diseases were examined. Results: LApBIN were sucessfully designed and prepared. Following oral administration of LApBIN, the nanoparticles could be sucessully orally adsorbed and translocated to monocytes. Contributed by the recruitment of monocytes to multiple obesity-related lesions, LApBIN successfully delivered bindarit to these lesions, and effectively suppressed inflammation there, which exerted successful preventive effects on high-fat-diet-induced obesity, insulin resistance, fatty liver and atherosclerosis. Conclusions:This strategy could represent a promising approach to develop effective oral treatments for obesity and other metabolic diseases.

ß-Caryophyllene Liposomes Attenuate Neurovascular Unit Damage After Subarachnoid Hemorrhage in Rats.

This study was conducted to prepare ß-caryophyllene loaded liposomes (BCP-LP) and investigated their effects on neurovascular unit (NVU) damage after subarachnoid hemorrhage (SAH) in rats. A blood injection into the pre-chiasmatic cistern was used to achieve SAH. BCP-LP were prepared, characterized and administrated to rats with SAH. The prepared BCP-LP were spherical with a size distribution of approximately 189.3 nm and Zeta potential of - 13.9 mV. Neurological scoring, the balance beam test, cerebral blood flow monitoring, brain edema and biochemical analyses were applied to evaluate the effects of BCP-LP on rat NVU damage after SAH. The results demonstrated that BCP-LP treatment improved neurological function disorder, balance ability and cerebral blood perfusion in rats. Brain edema detection and blood-brain barrier permeability detection revealed that BCP-LP could reduce brain edema and promote repairment of blood-brain barrier after SAH. Using the western blot experiments, we demonstrated that BCP-LP attenuated the loss of tight junction proteins Occludin and Zonula occludens-1, inhibit the high expression of VEGFR-2 and GFAP, and promote the repair of laminin. These results demonstrate the protective effect BCP-LP exert in the NVU after SAH in rats, and supports the use of BCP-LP for future study and therapy of SAH.

Apolipoprotein E Deficiency Aggravates Neuronal Injury by Enhancing Neuroinflammation via the JNK/c-Jun Pathway in the Early Phase of Experimental Subarachnoid Hemorrhage in Mice.

Neuronal injury is the primary cause of poor outcome after subarachnoid hemorrhage (SAH). The apolipoprotein E (APOE) gene has been suggested to be involved in the prognosis of SAH patients. However, the role of APOE in neuronal injury after SAH has not been well studied. In this study, SAH was induced in APOE-knockout (APOE-/-) and wild-type (WT) mice to investigate the impact of APOE deficiency on neuronal injury in the early phase of SAH. The experiments of this study were performed in murine SAH models in vivo and primary cultured microglia and neurons in vitro. The SAH model was induced by endovascular perforation in APOE-/- and APOE WT mice. The mortality rate, weight loss, and neurological deficits were recorded within 72 h after SAH. The neuronal injury was assessed by detecting the neuronal apoptosis and axonal injury. The activation of microglia was assessed by immunofluorescent staining of Iba-1, and clodronate liposomes were used for inhibiting microglial activation. The expression of JNK/c-Jun was evaluated by immunofluorescent staining or western blotting. The expression of TNF-α, IL-1ß, and IL-6 was evaluated by ELISA. Primary cultured microglia were treated with hemoglobin (Hb) in vitro for simulating the pathological process of SAH. SP600125, a JNK inhibitor, was used for evaluating the role of JNK in neuroinflammation. Nitrite production was detected for microglial activation, and flow cytometry was performed to detect apoptosis in vitro. The results suggested that SAH induced early neuronal injury and neurological deficits in mice. APOE deficiency resulted in more severe neurological deficits after SAH in mice. The neurological deficits were associated with exacerbation of neuronal injury, including neuronal apoptosis and axonal injury. Moreover, APOE deficiency enhanced microglial activation and related inflammatory injury on neurons. Inhibition of microglia attenuated neuronal injury in mice, whereas inhibition of JNK inhibited microglia-mediated inflammatory response in vitro. Taken together, JNK/c-Jun was involved in the enhancement of microglia-mediated inflammatory injury in APOE-/- mice. APOE deficiency aggravates neuronal injury which may account for the poor neurological outcomes of APOE-/- mice. The possible protective role of APOE against EBI via the modulation of inflammatory response indicates its potential treatment for SAH.

Curcumin Decreases Hyperphosphorylation of Tau by Down-Regulating Caveolin-1/GSK-3ß in N2a/APP695swe Cells and APP/PS1 Double Transgenic Alzheimer's Disease Mice.

Caveolin-1, the marker protein of membranal caveolae, is not only involved in cholesterol regulation, but also participates in the cleavage of amyloid [Formula: see text]-protein precursor (APP) and the generation of [Formula: see text]-amyloid peptide. It has been reported to be tightly related with Tau. In our previous studies, curcumin has been confirmed to play a neuroprotective role in Alzheimer's disease (AD), but its effects on Caveolin-1, Tau and their correlation, and the mechanism is still unknown. As such, in the present study, N2a/WT cells, N2a/APP695swe cell and six-month-old APP/PS1 double transgenic mice were enrolled. After curcumin treatment, the expression of Caveolin-1, Tau and their relationship was detected, and the potential mechanisms were explored. The results showed that in the N2a/APP695swe cells, curcumin not only decreased the number of caveolae, but also made their membrane to be thinner; and curcumin could decreased the expression of phosphorylated Tau (P-Tau(ser404)/Tau) and Caveolin-1 ([Formula: see text]), but the expression of phosphorylated GSK-3[Formula: see text] (P-GSK-3[Formula: see text]/GSK-3[Formula: see text] was increased ([Formula: see text]). In APP/PS1 transgenic mice, the same results were observed. Taken together, our data suggest that curcumin may play an important role in AD via reducing Caveolin-1, inactivating GSK-3[Formula: see text] and inhibiting the abnormal excessive phosphorylation of Tau, which will provide a new theory for AD treatment with curcumin.

ApoE Influences the Blood-Brain Barrier Through the NF-κB/MMP-9 Pathway After Traumatic Brain Injury.

Apolipoprotein E (ApoE), encoded by the ApoE gene (APOE), influences the outcomes of traumatic brain injury (TBI), but the mechanism remains unclear. The present study aimed to investigate the effects of different ApoEs on the outcome of TBI and to explore the possible mechanisms. Controlled cortical impact (CCI) was performed on APOEε3 (E3) and APOEε4 (E4) transgenic mice, APOE-KO (KO) mice, and wild type (WT) mice to construct an in vivo TBI model. Neurological deficits, blood brain barrier (BBB) permeability and brain edema were detected at days 1, 3, and 7 after TBI. The results revealed no significant differences among the four groups at day 1 or day 3 after injury, but more severe deficits were found in E4 and KO mice than in E3 and WT mice. Furthermore, a significant loss of tight junction proteins was observed in E4 and KO mice compared with E3 and WT mice at day 7. Additionally, more expression and activation of NF-κB and MMP-9 were found in E4 mice compared with E3 mice. Different ApoEs had distinct effects on neuro-function and BBB integrity after TBI. ApoE3, but not E4, might inhibit the NF-κB/MMP-9 pathway to alleviate BBB disruption and improve TBI outcomes.

ß-Caryophyllene/Hydroxypropyl-ß-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway.

This work was conducted to prepare ß-caryophyllene-hydroxypropyl-ß-cyclodextrin inclusion complex (HPßCD/BCP) and investigate its effects and mechanisms on cognitive deficits in vascular dementia (VD) rats. First, HPßCD/BCP was prepared, optimized, characterized, and evaluated. HPßCD/BCP and AM630 were then administered to VD rats to upregulate and downregulate the cannabinoid receptor type 2 (CB2). Results showed that HPßCD/BCP can significantly increase the bioavailability of BCP. Through the Morris water maze test, HPßCD/BCP can attenuate learning and memory deficits in rats. Cerebral blood flow (CBF) monitoring results indicated that HPßCD/BCP can promote the recovery of CBF. Moreover, molecular biology experiments showed that HPßCD/BCP can increase the expression levels of CB2 in brain tissues, particularly the hippocampus and white matter tissues, as well as the expression levels of PI3K and Akt. Overall, the findings demonstrated the protective effects of HPßCD/BCP against cognitive deficits induced by chronic cerebral ischemia and suggested the potential of HPßCD/BCP in the therapy of vascular dementia in the future.

Bexarotene protects against traumatic brain injury in mice partially through apolipoprotein E.

Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout (APOE-KO) mice. After CCI, mice were daily dosed with bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side-effects were all measured. The results showed that, after CCI, bexarotene treatment markedly improved the motor function and spatial memory in C57BL/6 compare to APOE-KO mice which showed no improvement. The inflammatory cytokines, microglia amount, cell apoptosis rate, and protein of cleaved caspase-3 around the injury site were markedly upregulated after TBI in both C57BL/6 and APOE-KO mice, and all these upregulation were significantly mitigated by bexarotene treatment in C57BL/6 mice, but not in APOE-KO mice. No side-effects were detected after consecutive administration. Taken together, bexarotene inhibits the inflammatory response as well as cell apoptosis and improves the neurological function of mice after TBI partially through apolipoprotein E. This may make it a promising candidate for the therapeutic treatment after TBI.

Peroxisome Proliferator-Activated Receptor ß/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats.

BACKGROUND AND PURPOSE: Early brain injury is proposed to be the primary cause of the poor outcome after subarachnoid hemorrhage (SAH), which is closely related to the neural apoptosis. To date, the relationship between peroxisome proliferator-activated receptor ß/δ (PPARß/δ) and nuclear factor-κB/matrix metalloproteinase-9 (NF-κB/MMP-9) pathway, both of which are closely related to apoptotic effects, has been poorly studied in SAH. The present study was undertaken to evaluate the effects of PPARß/δ on early brain injury and NF-κB/MMP-9 pathway after SAH in rats. METHODS: SAH model was established by injecting nonheparinized autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Adenoviruses or small interfering RNAs were injected into the right lateral cerebral ventricle to, respectively, up- or downregulate PPARß/δ expression before SAH. All animals were assessed with a neurological score and then killed at 24 hours after SAH surgery. The indexes of brain water content, blood-brain barrier permeability, and apoptosis were used to detect brain injury. The expression of PPARß/δ, NF-κB, and MMP-9 were measured by immunohistochemistry, gelatin zymography, and Western Blot methods, respectively. In addition, GW0742, a specific agonist of PPARß/δ, was used to treat SAH in rats, the effects of which were evaluated by neurological scoring and Evans blue extravasation. RESULTS: Overexpression of PPARß/δ by adenoviruses treatment significantly ameliorated brain injury with improvement in neurological deficits, brain edema, blood-brain barrier impairment, and neural cell apoptosis at 24 hours after SAH in rats, whereas downregulation of PPARß/δ by small interfering RNAs administration resulted in the reverse effects of the above. The expression levels of NF-κB and MMP-9 were markedly downregulated when PPARß/δ increased after PPARß/δ adenovirus transfection and upregulated when PPARß/δ decreased by PPARß/δ small interfering RNAs treatment. Moreover, GW0742 improved neurological deficits and reduced Evans blue extravasation at 24 hours after SAH. CONCLUSIONS: PPARß/δ's overexpression may attenuate early brain injury after rats' SAH administration, which reduces neural apoptosis possibly through blocking NF-κB/MMP-9 pathway.

Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice.

Autophagy is a lysosomal degradation pathway, which is essential for cell survival, proliferation, differentiation and homeostasis. It is well known that beta-amyloid (Aß) aggregation is one of key characteristics for Alzheimer's disease (AD), which triggers a complex pathological cascade, leading to neurodegeneration. Recent studies have shown that Aß peptide is generated from amyloid ß precursor protein (APP) during autophagic turnover of APP-rich organelles by autophagy. Aß generation during normal autophagy is subsequently degraded by lysosomes. Curcumin, a nature plant extraction, has been reported to inhibit the generation and deposition of Aß; however, the underlying mechanisms are not fully understood yet. In the present study, we reported that curcumin treatment not only attenuated cognitive impairment detected by Morris water maze test, but also inhibited the generation of Aß investigated by immunohistochemistry in APP/PS1 double transgenic AD mice. Moreover, curcumin induced autophagy in the mice, evidenced by LC3 immunofluorescence analysis and western blot assays on LC3. Furthermore, we found that curcumin significantly decreased the expression of Phosphatidylinositol 3-Kinase (PI3K), phosphorylated Akt and rapamycin (mTOR) at protein levels, respectively. Taken together, our data suggests that curcumin inhibits Aß generation and induces of autophagy by downregulating PI3K/Akt/mTOR signaling pathway, and further shows a neuroprotective effect. Meanwhile curcumin might be a candidate neuroprotective agent for AD patients treatment by inducing autophagy.