Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice.

Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1ß secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1ß, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice.

Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1ß production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1ß production with an IC50 value of 0.71 µM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors.

[Endovascular treatment of ruptured intracranial very small aneurysms].

OBJECTIVE: To explore the technique of endovascular therapy for ruptured intracranial very small aneurysms and evaluate the feasibility and safety of endovascular treatment of such aneurysms. METHODS: Twenty-two intracranial very small aneurysms in 22 patients with subarachnoid hemorrhage undergoing endovascular therapy were reviewed retrospectively. Their clinical, imaging, interventional and follow-up data were analyzed. Among them, there were 13 males and 9 females with a mean age of 54.5 years old. The Hunt-Hess grade was as follows: Grades I and II (n = 12) and Grades III and IV (n = 10). The locations of aneurysms were as follows: anterior communicating artery (n = 7), middle cerebral artery (n = 2), posterior communicating artery (n = 8) and internal carotid artery (n = 5). All aneurysms were embolized with coils. Among them, 7 received stent assistance and 2 balloon remodeling. RESULTS: Among 22 coiled aneurysms, complete occlusion was achieved in 17 aneurysms, neck remnant occurred in 1 patient and aneurysm remnant in 4 patients. Two aneurysms ruptured during coiling and one patient died from it. One patient had transient hemiparesis. All patients received a follow-up of 3 - 36 months and there was no recurrent hemorrhage. CONCLUSION: Endovascular treatment of ruptured intracranial very small aneurysms seems to be technically feasible, relatively safe and practically effective. An appropriate selection of interventional materials and use of sophisticated techniques yield an excellent outcome.

Three-dimensional volume-rendering technique in the angiographic follow-up of intracranial aneurysms embolized with coils.

OBJECT: The authors conducted a study to evaluate the advantages of a 3D volume-rendering technique (VRT) in follow-up digital subtraction (DS) angiography of coil-embolized intracranial aneurysms. METHODS: One hundred nine patients with 121 intracranial aneurysms underwent endovascular coil embolization and at least 1 follow-up DS angiography session at the authors' institution. Two neuroradiologists independently evaluated the conventional 2D DS angiograms, rotational angiograms, and 3D VRT images obtained at the interventional procedures and DS angiography follow-up. If multiple follow-up sessions were performed, the final follow-up was mainly considered. The authors compared the 3 techniques for their ability to detect aneurysm remnants (including aneurysm neck and sac remnants) and parent artery stenosis based on the angiographic follow-up. The Kruskal-Wallis test was used for group comparisons, and the kappa test was used to measure interobserver agreement. Statistical analyses were performed using commercially available software. RESULTS: There was a high statistical significance among 2D DS angiography, rotational angiography, and 3D VRT results (X(2) = 9.9613, p = 0.0069) when detecting an aneurysm remnant. Further comparisons disclosed a statistical significance between 3D VRT and rotational angiography (X(2) = 4.9754, p = 0.0257); a high statistical significance between 3D VRT and 2D DS angiography (X(2) = 8.9169, p = 0.0028); and no significant difference between rotational angiography and 2D DS angiography (X(2) = 0.5648, p = 0.4523). There was no statistical significance among the 3 techniques when detecting parent artery stenosis (X(2) = 2.5164, p = 0.2842). One case, in which parent artery stenosis was diagnosed by 2D DS angiography and rotational angiography, was excluded by 3D VRT following observations of multiple views. The kappa test showed good agreement between the 2 observers. CONCLUSIONS: The 3D VRT is more sensitive in detecting aneurysm remnants than 2D DS angiography and rotational angiography and is helpful for identifying parent artery stenosis. The authors recommend this technique for the angiographic follow-up of patients with coil-embolized aneurysms.

The effectiveness and feasibility of endovascular coil embolization for very small cerebral aneurysms: mid- and long-term follow-up.

BACKGROUND: Endovascular embolization for very small cerebral aneurysms (VSCAs) is still controversial. We report our experience with endovascular coil embolization for these lesions and assess the feasibility and effectiveness. METHODS: We conducted a review of our experience with endovascular treatment of a series of 19 patients with 20 VSCAs, located at the supraclinoid segment of the internal cranial artery (ICA) in seven, the cavernous ICA segment in three, the anterior communicating artery in five, vertebral artery-posterior inferior cerebellar artery in two, bifurcation of the middle cerebral artery in one, the pericallosal artery in one, and the P2 segment in one. The World Federation of Neurosurgical Societies classification before treatment was grade I in 14 patients and grade II in five patients. The strategy of endovascular treatment included coil occlusion, balloon-assisted coiling, and stent-assisted coiling. Occlusion rate was divided into (1) total/near total, occlusion rate 95-100%; (2) subtotal, occlusion rate 80-95%; and (3) partial, occlusion rate<80%. Clinical outcome of patients with ruptured aneurysm was ascertained according to the Glasgow Outcomes Scale. RESULTS: All patients were successfully treated with coil embolization; immediate angiography determined occlusion of the aneurysm, including total occlusion in five, subtotal occlusion in nine, and partial occlusion in six. During 1-2 years of follow-up, all aneurysms were confirmed as complete occlusion by control angiography. No recurrence or coil compaction occurred. No rehemorrhage or ischemic stroke occurred. CONCLUSION: Endovascular coil embolization for VSCAs is effective and feasible. Initial subtotal or partial aneurysm occlusion might progress to total occlusion.

Large-cohort comparison between three-dimensional time-of-flight magnetic resonance and rotational digital subtraction angiographies in intracranial aneurysm detection.

BACKGROUND AND PURPOSE: The value of MR angiography varies in diagnosis of intracranial aneurysms due to the difference of equipment and imaging technique. This study was to compare the effectiveness of 3-dimensional time-of-flight MR angiography at 3 T and rotational digital subtraction angiography, both with volume rendering (VR), in detecting intracranial aneurysms. METHODS: One hundred thirty-eight patients with suspected or known aneurysms and other cerebral vascular diseases detected by MR angiography underwent digital subtraction angiography examinations. Postprocessing techniques, including VR and the single artery highlighting method, were performed by a 3-dimensional specialist. The VR-digital subtraction angiography was obtained as the gold standard. RESULTS: The rotational digital subtraction angiography and VR-digital subtraction angiography revealed 146 aneurysms in 122 patients and no aneurysms in 16 patients. Of the 276 vessels examined, 136 vessels had 146 aneurysms and 140 vessels had none. Per vessel and per aneurysm sensitivities were 100%, whereas the per vessel accuracy ranged from 97.5% to 98.6% and the per aneurysm accuracy ranged from 95.1% to 97.0%. CONCLUSIONS: VR 3-dimensional time-of-flight MR angiography at 3 T has excellent sensitivity, accuracy, and correlation with VR-digital subtraction angiography and is comparable to catheter cerebral angiography for the evaluation of patients with intracranial aneurysms who tolerate MR angiography well.

[Effect of the oil from ganoderma lucidum spores on pathological changes in the substantia nigra and behaviors of MPTP-treated mice].

OBJECTIVE: To investigate the oil from the spores of ganoderma lucidum, a rare Chinese herb, on the behaviors and pathological changes in the substantia nigra pars compacta (SNpc) in mouse models of Parkinson's disease (PD) induced by MPTP. METHODS: C57BL mice were divided into 3 groups, and the ganoderma spores oil + MPTP group were treated with ganoderma spores oil for 8 days, together with subcutaneous injection of MPTP (30 mg/kg) starting on the third day for 6 days; MPTP group were pretreated with normal saline before subcutaneous MPTP injection, and the normal control group received pretreatment with normal saline before subcutaneous normal saline injection. The behavioral changes of the mice in different groups were observed by pole test, dopamine and its metabolic products in the striatum determined by HPLC, tyrosine hydroxylase (TH) positive cells detected by immunofluorescence method, and expression of TH protein by Western blotting. RESULTS: The mice in the ganoderma spores oil + MPTP group presented significantly less involuntary movement of the limbs in the pole test than the mice in MPTP group. The levels of dopamine and DOPAC in the striatum of ganoderma spores oil-treated mice were increased as compared with those in MPTP group. The number of surviving TH-positive neurons in SNpc of mice in ganoderma spores oil + MPTP group was significantly greater than that in MPTP group, with also significantly increased TH protein expression. CONCLUSION: Ganoderma spores oil has neuroprotective effect for preventing doparminergic neuron from impairment by MPTP.