Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion.

BACKGROUND: Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited. METHODS: We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications. RESULTS: Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P<0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation. CONCLUSIONS: In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

NLRP3 Inflammasome Activation Mediates Hepatitis E Virus-Induced Neuroinflammation.

Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1ß and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1ß and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.

UiO-66 nanoparticles combat influenza A virus in mice by activating the RIG-I-like receptor signaling pathway.

The Influenza A virus (IAV) is a zoonotic pathogen that infects humans and various animal species. Infection with IAV can cause fever, anorexia, and dyspnea and is often accompanied by pneumonia characterized by an excessive release of cytokines (i.e., cytokine storm). Nanodrug delivery systems and nanoparticles are a novel approach to address IAV infections. Herein, UiO-66 nanoparticles (NPs) are synthesized using a high-temperature melting reaction. The in vitro and in vivo optimal concentrations of UiO-66 NPs for antiviral activity are 200 µg mL-1 and 60 mg kg-1, respectively. Transcriptome analysis revealed that UiO-66 NPs can activate the RIG-I-like receptor signaling pathway, thereby enhancing the downstream type I interferon antiviral effect. These NPs suppress inflammation-related pathways, including the FOXO, HIF, and AMPK signaling pathways. The inhibitory effect of UiO-66 NPs on the adsorption and entry of IAV into A549 cells is significant. This study presents novel findings that demonstrate the effective inhibition of IAV adsorption and entry into cells via UiO-66 NPs and highlights their ability to activate the cellular RIG-I-like receptor signaling pathway, thereby exerting an anti-IAV effect in vitro or in mice. These results provide valuable insights into the mechanism of action of UiO-66 NPs against IAV and substantial data for advancing innovative antiviral nanomedicine.

Vital role of oxidative stress in tadpole liver damage caused by polystyrene nanoparticles.

Polystyrene nanoparticles are emerging as contaminants in freshwater environments, posing potential risks to amphibians exposed to extended periods of water contamination. Using tadpoles as a model, this study aimed to evaluate the toxicity of PS NPs. Pyrolysis-gas chromatography-tandem mass spectrometry (Py-GCMS) analysis revealed a concentration-dependent increase in polystyrene nanoparticles (PS NPs) levels in tadpoles with escalating exposure concentrations. Following exposure to 100 nm fluorescent microspheres, fluorescence was observed in the intestines and gills, peaking at 48 hours. Histopathological analysis identified degenerative necrosis and inflammation in the liver, along with atrophic necrosis of glomeruli and tubules in the kidneys. These results indicate a discernible impact of PS NPs on antioxidant levels, including reduced superoxide dismutase and catalase activities, elevated glutathione content, and increased malondialdehyde levels. Electron microscopy observations revealed the infiltration of PS NPs into Kupffer's cells and hepatocytes, leading to visible lesions such as nuclear condensation and mitochondrial disruption. The primary objective of this research was to elucidate the adverse effects of prolonged PS NPs exposure on amphibians.

Zeolitic Imidazolate Framework-8 Triggers the Inhibition of Arginine Biosynthesis to Combat Methicillin-Resistant Staphylococcus Aureus.

The self-preservation and intelligent survival abilities of methicillin-resistant Staphylococcus aureus (MRSA) result in the ineffective treatment of many antibiotics. Nano-drug delivery systems have emerged as a new strategy to overcome MRSA infection. ZIF-8 nanoparticles (ZIF-8 NPs) exhibit good antibacterial activities, while its molecular mechanisms are largely elusive. In this study, the ZIF-8 NPs are prepared using the room temperature solution reaction method. The values of minimum inhibitory concentration of ZIF-8 NPs against Escherichia coli and MRSA isolates are 25 and 12.5 µg mL-1 , respectively. Transcriptome and metabonomic analyses reveal that ZIF-8 NPs could trigger the inhibition of arginine biosynthesis pathway and the production of ROS, which lead to dysfunctional tricarboxylic acid cycle and disruption of cell membrane integrity, eventually killing MRSA isolates. Moreover, ZIF-8 NPs show desirable treatment and repair effects on mice model of MRSA isolates wound infected-model. The results, for the first time, reveal that the inhibition of arginine biosynthesis mediates the production of ROS and energy metabolism dysfunction contributes to the antibacterial ability of ZIF-8 NPs against MRSA. This study offers a new insight into ZIF-8 NPs combating MRSA isolates.

Novel synergistic mechanism of 11-keto-ß-boswellic acid and Z-Guggulsterone on ischemic stroke revealed by single-cell transcriptomics.

Although strides have been made, the challenge of preventing and treating ischemic stroke continues to persist globally. For thousands of years, the natural substances Frankincense and Myrrh have been employed in Chinese and Indian medicine to address cerebrovascular diseases, with the key components of 11-keto-ß-boswellic acid (KBA) and Z-Guggulsterone (Z-GS) being the active agents. In this study, the synergistic effect and underlying mechanism of KBA and Z-GS on ischemic stroke were examined using single-cell transcriptomics. Fourteen cell types were identified in KBA-Z-GS-treated ischemic penumbra, and microglia and astrocytes account for the largest proportion. They were further re-clustered into six and seven subtypes, respectively. GSVA analysis reflected the distinct roles of each subtype. Pseudo-time trajectory indicated that Slc1a2 and Timp1 were core fate transition genes regulated by KBA-Z-GS. In addition, KBA-Z-GS synergistically regulated inflammatory reactions in microglia and cellular metabolism and ferroptosis in astrocytes. Most notably, we established an innovative drug-gene synergistic regulation pattern, and genes regulated by KBA-Z-GS were divided into four categories based on this pattern. Finally, Spp1 was demonstrated as the hub target of KBA-Z-GS. Taken together, this study reveals the synergistic mechanism of KBA and Z-GS on cerebral ischemia, and Spp1 may be the synergistic target for that. Precise drug development targeting Spp1 may offer a potential therapeutic approach for treating ischemic stroke.

Advances of phytotherapy in ischemic stroke targeting PI3K/Akt signaling.

The pathogenesis of ischemic stroke is complex, and PI3K/Akt signaling is considered to play a crucial role in it. The PI3K/Akt pathway regulates inflammation, oxidative stress, apoptosis, autophagy, and vascular endothelial homeostasis after cerebral ischemia; therefore, drug research targeting the PI3K/Akt pathway has become the focus of scientists. In this review, we analyzed the research reports of antiischemic stroke drugs targeting the PI3K/Akt pathway in the past two decades. Because of the rich sources of natural products, increasing studies have explored the value of natural compounds, including Flavonoids, Quinones, Alkaloids, Phenylpropanoids, Phenols, Saponins, and Terpenoids, in alleviating neurological impairment and achieved satisfactory results. Herbal extracts and medicinal formulas have been applied in the treatment of ischemic stroke for thousands of years in East Asian countries. These precious clinical experiences provide a new avenue for research of antiischemic stroke drugs. Finally, we summarize and discuss the characteristics and shortcomings of the current research and put forward prospects for further in-depth exploration.

Comparison of the pharmacokinetics of Crocin-I in normoxic and hypoxic rats.

An ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS) method for the simultaneous determination of Crocin-I and its primary metabolites Crocetin was established, and a comparison of metabolic characteristics in vivo is made to Crocin-I and Crocetin in normoxic and hypoxic rats after intragastric administration. The acute hypoxic rat model was established by simulating high altitude environment in a hypobaric hypoxia animal experimental chamber. After intragastric administration of 400 mg•kg-1 Crocin-I. UPLC-Q-TOF-MS method was used to detect the plasma concentrations of Crocin-I and Crocetin in plasma at different times. Compared with normoxic rats, the area under the curve (AUC), mean residence time (MRT), time to peak (Tmax), half-life (T1/2) and plasma concentration (Cmax) of plasma Crocin-I in hypoxic rats were significantly increased (P < 0.01). The apparent distribution (Vz/F) and clearance (CLz/F) of plasma Crocin-I in hypoxic rats were significantly decreased (P < 0.01). Under hypoxic conditions, the pharmacokinetic parameters of Crocin-I and its metabolite Crocetin change significantly. The results provide a theoretical basis for the feasibility of Crocin-I for anti-hypoxia treatment in terms of pharmacokinetics and provide an essential experimental basis for optimizing the drug dosing regimen.

Preparation of CPD Photolyase Nanoliposomes Derived from Antarctic Microalgae and Their Effect on UVB-Induced Skin Damage in Mice.

UVB radiation is known to trigger the block of DNA replication and transcription by forming cyclobutane pyrimidine dimer (CPD), which results in severe skin damage. CPD photolyase, a kind of DNA repair enzyme, can efficiently repair CPDs that are absent in humans and mice. Although exogenous CPD photolyases have beneficial effects on skin diseases, the mechanisms of CPD photolyases on the skin remain unknown. Here, this study prepared CPD photolyase nanoliposomes (CPDNL) from Antarctic Chlamydomonas sp. ICE-L, which thrives in harsh, high-UVB conditions, and evaluated their protective mechanisms against UVB-induced damage in mice. CPDNL were optimized using response surface methodology, characterized by a mean particle size of 105.5 nm, with an encapsulation efficiency of 63.3%. Topical application of CPDNL prevented UVB-induced erythema, epidermal thickness, and wrinkles in mice. CPDNL mitigated UVB-induced DNA damage by significantly decreasing the CPD concentration. CPDNL exhibited antioxidant properties as they reduced the production of reactive oxygen species (ROS) and malondialdehyde. Through activation of the NF-κB pathway, CPDNL reduced the expression of pro-inflammatory cytokines including IL-6, TNF-α, and COX-2. Furthermore, CPDNL suppressed the MAPK signaling activation by downregulating the mRNA and protein expression of ERK, JNK, and p38 as well as AP-1. The MMP-1 and MMP-2 expressions were also remarkably decreased, which inhibited the collagen degradation. Therefore, we concluded that CPDNL exerted DNA repair, antioxidant, anti-inflammation, and anti-wrinkle properties as well as collagen protection via regulation of the NF-κB/MAPK/MMP signaling pathways in UVB-induced mice, demonstrating that Antarctic CPD photolyases have the potential for skincare products against UVB and photoaging.

Association between tirofiban monotherapy and efficacy and safety in acute ischemic stroke.

BACKGROUND: Studies have suggested that glycoprotein IIb/IIIa antagonists such as tirofiban are beneficial for patients with acute coronary syndromes. However, it is still uncertain about the efficacy and safety of tirofiban in patients with acute ischemic stroke (AIS). METHODS: In this prospective non-randomized study, 255 AIS patients were recruited from 4 comprehensive stroke centers in China between January, 2017 and May, 2018. Among them,169 patients were treated with aspirin plus clopidogrel and 86 patients were treated with tirofiban. The primary functional outcome was the distribution of the 90 days' modified Rankin Scale (mRS). The safety outcomes included the incidence of intracranial hemorrhage (ICH) at discharge and mortality at 3 months. RESULTS: In the propensity score matched cohort, tirofiban alone was noninferior to the dual antiplatelet with regard to the primary outcome (adjusted common odds ratio, 0.97; 95% confidence interval, 0.46 to 2.04; P = 0.93). Mortality at 90 days was 10% in the dual antiplatelet group and 8% in the tirofiban group (adjusted odds ratio 0.75; 95% CI 0.08 to 7.40, p = 0.81). There was no difference of the ICH rate between two groups (adjusted odds ratio 0.44; 95% CI 0.13 to 1.48, p = 0.18). In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar differences were found for functional and safety outcomes. CONCLUSIONS: Our study suggested that tirofiban use appears to be safe as monotherapy in AIS treatment compared with common dual antiplatelet therapy, however, no improvement in functional outcomes was found. TRIAL REGISTRATION: Chinese clinical trial registry, ChiCTR2000034443 , 05/07/2020. Retrospectively registered.

Efficacy and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Liver Disease: a Meta-Analysis and Systematic Review.

BACKGROUND: Liver disease is associated with increased bleeding risk. The efficacy and safety of direct oral anticoagulants (DOACs) is a subject of contention in atrial fibrillation (AF) patients with liver disease. METHODS: Electronic databases (PubMed, Embase, and Cochrane Library) were searched to retrieve studies on the efficacy and safety of DOACs versus warfarin in AF patients with liver disease from January 1980 to April 2020. A meta-analysis was conducted using a random-effects model. RESULTS: Six studies involving 41,859 patients were included. Compared with warfarin, DOACs demonstrated significant reduction in ischemic stroke (HR, 0.68; 95% CI (0.54-0.86)), major bleeding (0.74 (0.59-0.92)), and intracranial hemorrhage (ICH) (0.48 (0.40-0.58)), with no significant effect on gastrointestinal bleeding (P = 0.893) in AF patients with liver disease. Similar results were observed in regular-dose, reduced-dose, and active liver disease subgroups, albeit Asian patients had a slight reduction in major bleeding (P = 0.055). Furthermore, the pooled estimates of individual DOAC subgroups indicated that dabigatran and apixaban led to greater safety in major bleeding (P < 0.001), ICH (P < 0.001), and gastrointestinal bleeding (P < 0.005) in these patients. The same trends were observed in AF patients with cirrhosis. CONCLUSIONS: Our findings suggest that DOACs significantly reduce the risk of ischemic stroke, major bleeding, and ICH, with no significant effect on the risk of gastrointestinal bleeding in AF patients with liver disease compared with warfarin.

Characterization of antimicrobial-resistant Staphylococcus aureus from retail foods in Beijing, China.

Staphylococcus aureus is an opportunistic pathogen leading to food poisoning as well as human infections. The present study examined the prevalence and characterization of antimicrobial-resistant S. aureus in sushi from 42 outlets and in pork products from eight outlets in Beijing, China. The total bacterial counts were between 3.0 and 8.9 log CFU/g (mean 5.5 ± 1.5 log CFU/g) in sushi products and 4.8 to 7.4 log CFU/g (mean 5.6 ± 0.8 log CFU/g) in pork products. The mean counts of coliforms were 2.7 and 2.9 log CFU/g in sushi and pork, respectively. Staphylococcus aureus was isolated from seven sushi outlets (13 isolates) and two pork outlets (2 isolates) with average counts below 2 log CFU/g in all cases. A total of 15 S. aureus isolates were further characterized. Six lineages of S. aureus were present, including ST398 (n = 5), ST25 (n = 4), ST15 (n = 2), ST59 (n = 2), ST8 (n = 1) and ST2631 (n = 1). Thirteen isolates contained the scn virulence marker, whereas four and eight isolates contained the virulence marker edinB and enterotoxin genes, respectively. Characterization of antimicrobial resistance profiles documented resistances to ampicillin (n = 15), penicillin (n = 14), ceftazidime (n = 6), erythromycin (n = 4), tetracycline (n = 3), clindamycin (n = 3), and gentamicin (n = 1). Three MRSA isolates were obtained, one from pork (ST398) and two from one sushi outlet (ST59). They were all resistant to at least three classes of antimicrobials and two of them contained the scn gene and enterotoxin genes. Twelve sushi isolates and one of the pork isolates contained the scn gene, indicating that they were of human origin. This emphasizes the potential importance of transmission through foods of antimicrobial-resistant S. aureus including MRSA. We also showed that S. aureus exhibited geographical variation with regards to ST profiles, antimicrobial-resistance and virulence genes when comparing isolates from sushi products sold in Beijing and Copenhagen, Denmark. Whereas food safety is not compromised by the presence of low amounts of S. aureus in sushi, this study shows that with regards to public health such foods may serve as vehicles for transmission of multidrug-resistant S. aureus and MRSA lineages.

Magnetic Three-Phase Single-Drop Microextraction for Rapid Amplification of the Signals of DNA and MicroRNA Analysis.

The detection of nucleic acids usually suffers from a lengthy amplification process. To obtain an enhanced signal within several seconds, a magnetic three-phase single-drop microextraction (MTP-SDME) approach was developed for the quantification of nucleic acids. First, a target-triggered recycling amplification strategy was used to constitute magnetic branched DNA/Fe3O4 networks, which displayed peroxidase-like catalytic activity toward the 3,3',5,5'-tetramethylbenzidine colorimetric reaction. The networks were separated and enriched by rapid (6 s) MTP-SDME (with only 6 µL of solvent required), thereby producing highly sensitive signals for the quantification of nucleic acids. The signals were significantly amplified by the triple strategy (network formation, MTP-SDME, and catalytic reaction). The application of magnetic extraction minimized the background signal, avoided sample matrix effects, and enhanced the analyte signals. This assay achieved linear calibration curves of between 0.5 aM and 1 pM for microRNA-122 (miRNA-122) and between 1 aM and 1 pM for HBV-T (a DNA fragment from hepatitis B virus). Limits of detection of 0.15 aM for miRNA-122 and 0.34 aM for HBV-T were attained, with relative standard deviations of <5.0% (n = 3). Furthermore, the procedure was applied to determine miRNA-122 and HBV-T in genuine serum samples from hepatocellular carcinoma patients.

Coixol Suppresses NF-κB, MAPK Pathways and NLRP3 Inflammasome Activation in Lipopolysaccharide-Induced RAW 264.7 Cells.

Coixol, a plant polyphenol extracted from coix (Coix lachryma-jobi L.var.ma-yuen Stapf), has not been investigated for its anti-inflammatory effect. In this study, using a lipopolysaccharide (LPS)-induced macrophage cell model, we observed that coixol can effectively reduce the expression of interleukin (IL)-1ß, IL-6, IL-18, tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthases (iNOS), and cyclooxygenase (COX)-2, but had no effect on the expression of the anti-inflammatory mediator IL-10. Furthermore, we found that coixol inhibits mitogen-activated protein kinases (MAPKs), nuclear transcription factor κ B (NF-κB) pathways, and NOD-like receptor protein (NLRP) 3 inflammasome activation. In conclusion, the present study demonstrates that coixol exerts certain anti-inflammatory effects by inhibiting the expression of pro-inflammatory mediators in vitro. The mechanism of this effect was in part related to its ability to inhibit the activation of NF-κB, MAPKs pathways, and NLRP3 inflammasome.

[Study on protective effect of vanillic acid from Astragalus membranaceus on hypertensive cardiac remodeling based on network pharmacology screen].

To identify and verify the active ingredients from Astragalus membranaceus on hypertensive cardiac remodeling based on network pharmacology and heart RNA-sequencing data. The monomers of A. membranaceus and their intervention target database were established by using network pharmacology. The genes associated to cardiac remodeling were then screened by analyzing cardiac RNA-sequencing data. An overlap between genes related to cardiac remodeling and targets of ingredients form A. membranaceus was collected to obtain monomers with protective effect on hypertensive cardiac remodeling. Angiotensin Ⅱ(AngⅡ)-induced mouse cardiac remodeling model was used to validate the protective effect of active ingredients from A. membranaceus on hypertensive cardiac remodeling. Finally, a total of 81 monomers and 1 197 targets were enrolled in our database. Mouse RNA-sequencing data showed that 983 genes were significantly up-regulated and 465 genes were down-regulation in myocardial tissues of the cardiac remodeling mice as compared with blank group mice, respectively. Ninety-two genes were found via overlapping between genes related to cardiac remodeling and targets, involving 59 monomers from A. membranaceus. Further research found that vanillic acid(VA) could intervene 27 genes associated with hypertensive cardiac remodeling, ranking top 1. Meanwhile, VA could significantly inhibit AngⅡ-induced increase in ratio of heart weight to body weight and heart weight to tibial length, ANP and BNP mRNA levels in myocardial tissues, myocardial tissue damage, cardiac fibrosis level and cardiac hypertrophy level in vivo. Those results showed that network pharmacology screen-based VA has protective effect on AngⅡ-induced cardiac remodeling.

Chronic heat stress negatively affects the immune functions of both spleens and intestinal mucosal system in pigs through the inhibition of apoptosis.

With the globe warming, chronic heat stress (CHS) has been considered to be a common hazard that could negatively affect pig's growth and reproduction performance. However, the effects of CHS on the immune functions of pigs were seldom reported, especially the cellular immune functions of intestinal mucosal system. In order to resolve this problem, a pig CHS model was built firstly and the effects of CHS on numbers of T cells in spleen and small intestines were observed. Exposure to a temperature of 39 °C, 4 h/d for 10d, the expression of heat stress protein 70 (HSP70) was increased dramatically. Under CHS condition, the numbers of CD3+ T cells were increased dramatically in both spleens and small intestines. Besides, the numbers of CD4+T cells and the value of CD4+/CD8+T cells in spleens were also significantly increased. The results highly revealed that CHS made the equilibrium state of immune function destroyed. Furthermore, CHS mainly promoted the expression of anti-apoptosis factor B cell lymphoma-2 (Bcl-2) and thus inhibited the apoptosis of lymphocytes in spleens and intestinal mucosa. This study demonstrates for the first time that CHS negatively affects the immune functions of both spleens and intestinal mucosal system in pigs through the inhibition of apoptosis. Our study can richer the data for study of mechanism of CHS and provide new knowledge for reference of making new strategy to control the disease induced by CHS.

Acetyl-11-keto-ß-boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF-ß/Smad signalling pathway.

Acetyl-11-keto-ß-boswellic acid (AKBA), an active triterpenoid compound from the extract of Boswellia serrate, has been reported previously in our group to alleviate fibrosis in vascular remodelling. This study aimed to elucidate the in vivo and in vitro efficacy and mechanism of AKBA in renal interstitial fibrosis. The experimental renal fibrosis was produced in C57BL/6 mice via unilateral ureteral obstruction (UUO). Hypoxia-induced HK-2 cells were used to imitate the pathological process of renal fibrosis in vitro. Results showed that the treatment of AKBA significantly alleviated UUO-induced impairment of renal function and improved the renal fibrosis by decreasing the expression of TGF-ß1, α-SMA, collagen I and collagen IV in UUO kidneys. In hypoxia-induced HK-2 cells, AKBA displayed remarkable cell protective effects and anti-fibrotic properties by increasing the cell viability, decreasing the lactate dehydrogenase (LDH) release and inhibiting fibrotic factor expression. Moreover, in obstructed kidneys and HK-2 cells, AKBA markedly down-regulated the expression of TGFß-RI, TGFß-RII, phosphorylated-Smad2/3 (p-Smad2/3) and Smad4 in a dose-dependent fashion while up-regulated the expression of Klotho and Smad7 in the same manner. In addition, the effects of AKBA on the Klotho/TGF-ß/Smad signalling were reversed by transfecting with siRNA-Klotho in HK-2 cells. In conclusion, our findings provide evidence that AKBA can effectively protect kidney against interstitial fibrosis, and this renoprotective effect involves the Klotho/TGF-ß/Smad signalling pathway. Therefore, AKBA could be considered as a promising candidate drug for renal interstitial fibrosis.

Z-Guggulsterone attenuates astrocytes-mediated neuroinflammation after ischemia by inhibiting toll-like receptor 4 pathway.

Inflammatory damage plays a pivotal role in ischemic stroke pathogenesis and may represent one of the therapeutic targets. Z-Guggulsterone (Z-GS), an active component derived from myrrh, has been used to treat various diseases. The traditional uses suggest that myrrh is a good candidate for anti-inflammatory damage. This study was to investigate the anti-inflammatory and neuroprotective effects of Z-GS following cerebral ischemic injury, as well as the exact mechanisms behind them. Rat middle cerebral artery occlusion (MCAO) model and in vitro astrocytes oxygen-glucose deprivation (OGD) model were adopted to simulate ischemic stroke. Z-GS (30 or 60 mg/kg) was administered intraperitoneally immediately after reperfusion, while astrocytes were maintained in 30 or 60 µM Z-GS before OGD treatment. The results indicated that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in vivo, and increased the astrocytes viability in vitro. Moreover, the treatment of Z-GS inhibited the astrocytes activation and down-regulated the mRNA levels of pro-inflammatory cytokines. Furthermore, the activated TLR4-NF-κB signaling pathways induced by MCAO or OGD were significantly suppressed by Z-GS treatment, which was achieved via inhibiting the phosphorylation of JNK. Our results demonstrated that Z-GS exerted neuroprotective and anti-inflammatory properties through preventing activation of TLR4-mediated pathway in the activated astrocytes after ischemia injury. Therefore, Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.

Identification of genes and pathways potentially related to PHF20 by gene expression profile analysis of glioblastoma U87 cell line.

BACKGROUND: Glioblastoma is the most common and aggressive brain tumor associated with a poor prognosis. Plant homeodomain finger protein 20 (PHF20) is highly expressed in primary human gliomas and its expression is associated with tumor grade. However, the molecular mechanism by which PHF20 regulates glioblastoma remains poorly understood. METHODS: Genome wide gene expression analysis was performed to identify differentially expressed genes (DEGs) in U87 cells with PHF20 gene knockdown. Gene ontology (GO) and pathway enrichment analyses were performed to investigate the functions and pathways of DEGs. Pathway-net and signal-net analyses were conducted to identify the key genes and pathways related to PHF20. RESULTS: Expression of 540 genes, including FEN1 and CCL3, were significantly altered upon PHF20 gene silencing. GO analysis results showed that DEGs were significantly enriched in small molecule metabolic and apoptotic processes. Pathway analysis indicated that DEGs were mainly involved in cancer and metabolic pathways. The MAPK, apoptosis and p53 signaling pathways were identified as the hub pathways in the pathway network, while PLCB1, NRAS and PIK3 s were hub genes in the signaling network. CONCLUSIONS: Our findings indicated that PHF20 is a pivotal upstream regulator. It affects the occurrence and development of glioma by regulating a series of tumor-related genes, such as FEN1, CCL3, PLCB1, NRAS and PIK3s, and activation of apoptosis signaling pathways. Therefore, PHF20 might be a novel biomarker for early diagnosis, and a potential target for glioblastoma therapies.

Layered MoS2 Hollow Spheres for Highly-Efficient Photothermal Therapy of Rabbit Liver Orthotopic Transplantation Tumors.

Combining photothermal therapy (PTT) with clinical technology to kill cancer via overcoming the low tumor targeting and poor therapy efficiency has great potential in basic and clinical researches. A brand-new MoS2 nanostructure is designed and fabricated, i.e., layered MoS2 hollow spheres (LMHSs) with strong absorption in near-infrared region (NIR) and high photothermal conversion efficiency via a simple and fast chemical aerosol flow method. Owing to curving layered hollow spherical structure, the as-prepared LMHSs exhibit unique electronic properties comparing with MoS2 nanosheets. In vitro and in vivo studies demonstrate their high photothermal ablation of cell and tumor elimination rate by single NIR light irradiation. Systematic acute toxicity study indicates that these LMHSs have negligible toxic effects to normal tissues and blood. Remarkably, minimally invasive interventional techniques are introduced to improve tumor targeting of PTT agents for the first time. To explore PTT efficiency on orthotopic transplantation tumors, New Zealand white rabbits with VX2 tumor in liver are used as animal models. The effective elimination of tumors is successfully realized by PTT under the guidance of digital subtraction angiography, computed tomography, and thermal imaging, which provides a new way for tumor-targeting delivery and cancer theranostic application.