Ferroptosis is a form of regulated non-apoptotic cell death that has been implicated in several disease contexts. A better understanding of the ferroptotic death mechanism could lead to the development of new therapeutics for degenerative diseases, and a better understanding of how to induce ferroptosis in specific tumor contexts. We performed an unbiased genome-wide siRNA screen to find genetic suppressors of ferroptosis. We determined that loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine-glutamate antiporter known as system xc(-). Knockdown of CARS inhibited erastin-induced death by preventing the induction of lipid reactive oxygen species, without altering iron homeostasis. Knockdown of CARS led to the accumulation of cystathionine, a metabolite on the transsulfuration pathway, and upregulated genes associated with serine biosynthesis and transsulfuration. In addition, inhibition of the transsulfuration pathway resensitized cells to erastin, even after CARS knockdown. These studies demonstrate a new mechanism of resistance to ferroptosis and may lead to strategies for inducing and suppressing ferroptosis in diverse contexts.
Malignant tumors pose a heavy threat to human health. In article number 2001704, Zhiqing Pang, Wuli Yang, and co‐workers present a multifunctional nanoplatform integrating platelet membrane with dual ferroptosis inducers for high‐performance ferroptosis‐enhanced immunotherapy of tumors. The biomimetic nanoparticles can not only make tumor ablation by ferroptosis, but also further awaken and boost immune cells to join forces to fight tumors.
This investigation was performed to determine the neuroprotective effect of baicalin on permanent cerebral ischemia injury in rats and the potential mechanisms in this process. Adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). The rats were then received intraperitoneal injection with baicalin (10, 30 and 100 mg/kg) or vehicle. Morphological characteristic, neurological deficit scores, cerebral infarct volume and the enzymatic activity of myeloperoxidase (MPO) were measured 24 h after pMCAO. The mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by RT-PCR. Neuronal apoptosis was determined by TUNEL staining and Western blot. Baicalin (30 and 100 mg/kg) reduced neurological deficit scores and cerebral infarct volume 24 h after pMCAO. Baicalin significantly decreased the enzymatic activity of MPO and the expression of iNOS mRNA and COX-2 mRNA in rat brain, it also significantly inhibited neuronal apoptosis and the expression of cleaved caspase-3 protein after pMCAO. Our results suggested that baicalin possesses potent anti-inflammatory and anti-apoptotic properties and attenuates cerebral ischemia injury. This protection might be associated with the downregulated expression of iNOS mRNA, COX-2 mRNA, and cleaved caspase-3 protein.
2This study was performed to investigate whether intensive antihypertensive treatment with achieved blood pressure (BP) 140/90 mm Hg, as compared with standard treatment with achieved BP 150/90 mm Hg, could further improve cardiovascular outcomes in Chinese hypertensive patients older than 70 years. A total of 724 participants were randomly assigned to intensive or standard antihypertensive treatment. After a mean follow-up of 4 years, the mean achieved BP was 135.7/76.2 mm Hg in the intensive treatment group and 149.7/82.1 mm Hg in the standard treatment group. The visit-to-visit variability in systolic BP and diastolic BP was lower in the intensive group than that in the standard group. Intensive antihypertensive treatment, compared with the standard treatment, decreased total and cardiovascular mortality by 41.7% and 50.3%, respectively, and reduced fatal/nonfatal stroke by 42.0% and heart failure death by 62.7%. Cox regression analysis indicated that the mean systolic BP (P=.020; 95% confidence interval, 1.006-1.069) and the standard deviation of systolic BP (P=.033; 95% confidence interval, 1.006-1.151) were risk factors for cardiovascular endpoint events. Intensive antihypertensive treatment with achieved 136/76 mm Hg was beneficial for Chinese hypertensive patients older than 70 years. Longterm visit-to-visit variability in systolic BP was positively associated with the incidence of cardiovascular events. J Clin Hypertens (Greenwich). 2013;15:420-427. ª2013 Wiley Periodicals, Inc.Hypertension is one of the most common diseases associated with the elderly. It is a significant risk factor for senile congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm and has become an important public-health challenge worldwide.1 The risks associated with hypertension are greater in older than in younger patients, and antihypertensive treatment is reported to be actually more cost-effective for the elderly.2 The results of the study for the Hypertension in the Very Elderly Trial (HYVET) suggest that antihypertensive treatment with the achieved blood pressure (BP) of 143.5/77.9 mm Hg was beneficial in hypertensive patients older than 80 years, associated with a 30% reduction in the rate of fatal or nonfatal stroke, a 39% reduction in the rate of death from stroke, a 21% reduction in the rate of death from any cause, a 23% reduction in the rate of death from cardiovascular causes, and a 64% reduction in the rate of heart failure, compared with the placebo group with the achieved BP of 158.5/84.0 mm Hg.3 Thus, BP reduction in preventing stroke and other cardiovascular events for elderly hypertensive patients has evoked great focus in the past decade. Although many guidelines for the management of hypertension proposed the goal of systolic BP (SBP) as <150 mm Hg for the elderly, 4,5 it is unclear whether further reduction is still beneficial. In addition, although it has been suggested that BP variability derived from 24-hour ambulatory monitoring may be an independent risk factor for ...
Recent work from our laboratory demonstrated that baicalin attenuates inflammatory reaction and cerebral ischemia injury in rats. Toll-like receptor 2 and 4 (TLR2/4) and the downstream nuclear factor-kappa B (NF-κB) signaling pathway, which mediate the inflammatory reaction, are involved in the pathophysiological processes of cerebral ischemia. In this study, we investigated whether baicalin inhibits TLR2/4 signaling pathway in a rat model of permanent focal cerebral ischemia. Adult Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO). Baicalin was administered by intraperitoneally injected twice at 2 and 12 h after the onset of ischemia. Cerebral infarct area and infarct volume were measured 24 h after MCAO. Expression of TLR2/4, NF-κB, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were determined by RT-PCR or western blot. NO and PGE2 production in rat brain were measured 24 h after MCAO. Serum content of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were detected by ELISA. Baicalin reduced cerebral infarct area and infarct volume. Baicalin reduced the expression of TLR2/4 and NF-κB, decreased the expression and activity of iNOS and COX-2 in rat brain. Baicalin also attenuated the serum content of TNF-α and IL-1β. Our results suggest that baicalin inhibits the TLR2/4 signaling pathway in cerebral ischemia, which may be a mechanism underlying the baicalin's neuroprotection.
Toll-like receptors (TLRs) are considered to mediate the inflammatory reaction, which are involved in the pathophysiological processes of cerebral ischemia injury. To elucidate the possible role of inflammatory reaction and TLR2/4 signaling pathway in cerebral ischemia, in the present study, we explored the spatio-temporal distribution of inflammatory reaction, and further investigated the time-course expression of TLR2/4 and the downstream effector molecules after focal cerebral ischemia in rats. Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO) for 6, 12, 24, 48 and 72 h. Neurological deficit, cerebral infarction and neutrophil infiltration were measured at different time points following pMCAO. Expression of TLR2/4 were examined by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) were determined by western blot. Serum content of tumor necrosis factor-alpha (TNF-alpha) was detected by enzyme-linked immunosorbent assay (ELISA). Experimental results showed that pMCAO caused an increase of neutrophil infiltration in infarcted brain tissue, with a peaked activity at 24 h of ischemia. The inflammatory molecules including TLR2, TLR4, NF-kappaB, COX-2 and TNF-alpha were significantly increased after pMCAO, especially during 12-24 h of ischemia, which were correlated with pMCAO-induced brain injury and cerebral inflammation. Our studies suggested that TLR2/4 signaling pathway likely aggravated ischemic brain injury through mediating the inflammatory reaction. TLR2/4 signaling pathway may be a promising therapeutic target for cerebral ischemia injury.
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