Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of ...macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI). The protective effect of IPC was abolished by pharmacological inhibitors of autophagy and by the ablation of Atg7 from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide induced autophagy and protected against IRI. These results suggest the dependence of IPC protection on renal autophagy. During IPC, the mitophagy regulator PINK1 (PTEN induced putative kinase 1) was activated. Both IPC and BECN1 peptide enhanced mitolysosome formation during renal IRI in mitophagy reporter mice, suggesting that IPC may protect kidneys by activating mitophagy. We further established an in vitro model of IPC by inducing 'chemical ischemia' in kidney proximal tubular cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Brief treatment with CCCP protected against subsequent injury in these cells and the protective effect was abrogated by autophagy inhibition. In vitro IPC increased mitophagosome formation, enhanced the delivery of mitophagosomes to lysosomes, and promoted the clearance of damaged mitochondria during subsequent CCCP treatment. IPC also suppressed mitochondrial depolarization, improved ATP production, and inhibited the generation of reactive oxygen species. Knockdown of Pink1 suppressed mitophagy and reduced the cytoprotective effect of IPC. Together, these results suggest that autophagy, especially mitophagy, plays an important role in the protective effect of IPC.
Abbreviations: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4ʹ,6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5ʹ,6,6ʹ-tetrachloro-1,1ʹ,3,3ʹ-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type ...microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.
•The mechanisms of buffer zone to improve the evacuation efficiency were studied.•Buffer zone plays a significant positive role at high desired velocity.•How the buffer zone reduces the density at ...the exit is interpreted.•The average velocity is positively correlated with the length of buffer zone.
To control overcrowded pedestrians at the exit, buffer zones are very common in densely populated areas. However, little focus has been paid on the mechanisms of buffer zone. In this paper, a tentative experiment was designed to preliminarily reveal the role of buffer zone in crowd evacuation. Then a social force based simulation model was established by Massmotion according to the properties of the experiment. The simulated results show that buffer zones may have a potential positive effect on evacuation through comparing with the experimental results. After that, via changing the buffer zone length and the desired velocity of agents in further simulations, the data, such as evacuation time, density distribution, individual waiting time, instantaneous velocity and average velocity were investigated in detail. It is found that after the buffer zone set, the evacuation efficiency is significantly improved at high desired velocity, and the evacuation time is shortened with the increase in buffer zone length. Setting buffer zone in front of the exit can effectively reduce the crowd density at the exit, alleviate the surgent transmission of density waves in crowd, so as to reduce the risk of crowd squeezing and trampling. Besides, when the desired velocity is relatively high, the relationship between the buffer zone length and the average velocity is obtained specifically, indicating that the longer the buffer zone, the more likely pedestrians can escape as quickly as possible. Based on this work, some suggestions were put forward on how to control the dense evacuation via setting suitable buffer zones.
Free fatty acids (FFAs) play important physiological roles in many tissues as an energy source and as signaling molecules in various cellular processes. Elevated levels of circulating FFAs are ...associated with obesity, dyslipidemia, and diabetes. Here we show that GPR84, a previously orphan G protein-coupled receptor, functions as a receptor for medium-chain FFAs with carbon chain lengths of 9-14. Medium-chain FFAs elicit calcium mobilization, inhibit 3′,5′-cyclic AMP production, and stimulate 35Sguanosine 5′-O-(3-thiotriphosphate) binding in a GPR84-dependent manner. The activation of GPR84 by medium-chain FFAs couples primarily to a pertussis toxin-sensitive Gi/o pathway. In addition, we show that GPR84 is selectively expressed in leukocytes and markedly induced in monocytes/macrophages upon activation by lipopolysaccharide. Furthermore, we demonstrate that medium-chain FFAs amplify lipopolysaccharide-stimulated production of the proinflammatory cytokine interleukin-12 p40 through GPR84. Our results indicate a role for GPR84 in directly linking fatty acid metabolism to immunological regulation.
Local catabolism of the essential amino acid tryptophan is considered an important mechanism in regulating immunological and neurological responses. The kynurenine pathway is the main route for the ...non-protein metabolism of tryptophan. The intermediates of the kynurenine pathway are present at micromolar concentrations in blood and are regulated by inflammatory stimuli. Here we show that GPR35, a previously orphan G protein-coupled receptor, functions as a receptor for the kynurenine pathway intermediate kynurenic acid. Kynurenic acid elicits calcium mobilization and inositol phosphate production in a GPR35-dependent manner in the presence of Gqi/o chimeric G proteins. Kynurenic acid stimulates 35Sguanosine 5′-O-(3-thiotriphosphate) binding in GPR35-expressing cells, an effect abolished by pertussis toxin treatment. Kynurenic acid also induces the internalization of GPR35. Expression analysis indicates that GPR35 is predominantly detected in immune cells and the gastrointestinal tract. Furthermore, we show that kynurenic acid inhibits lipopolysaccharide-induced tumor necrosis factor-α secretion in peripheral blood mononuclear cells. Our results suggest unexpected signaling functions for kynurenic acid through GPR35 activation.
Neuroinflammation, marked by gliosis and infiltrating T cells, is a prominent pathological feature in diverse models of dominantly inherited neurodegenerative diseases. Recent evidence derived from ...transgenic mice ubiquitously overexpressing mutant Cu²⁺/Zn²⁺ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), indicates that glia with either a lack of or reduction in mSOD1 expression enhance motoneuron protection and slow disease progression. However, the contribution of T cells that are present at sites of motoneuron injury in mSOD1 transgenic mice is not known. Here we show that when mSOD1 mice were bred with mice lacking functional T cells or CD4+ T cells, motoneuron disease was accelerated, accompanied by unexpected attenuated morphological markers of gliosis, increased mRNA levels for proinflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters. Bone marrow transplants reconstituted mice with T cells, prolonged survival, suppressed cytotoxicity, and restored glial activation. These results demonstrate for the first time in a model of chronic neurodegeneration that morphological activation of microglia and astroglia does not predict glial function, and that the presence of CD4+ T cells provides supportive neuroprotection by modulating the trophic/cytotoxic balance of glia. These glial/T-cell interactions establish a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.
ObjectivesTo explore the prevalence, awareness, treatment and control rate of hypertension and analyse the potential social environment factors among Ngawa Tibetans in China.DesignThis was a ...cross-sectional observational study.SettingThe investigation based on a multistage stratified cluster sampling was conducted in the Ngawa area, Sichuan Province, Southwest China. Tibetan residents were selected by random sampling method from one city and six counties in Ngawa.MethodsBasic demographical information, physical activity and blood pressure were collected. In addition, the participants completed the questionnaire. A multivariate logistic regression analysis was used to examine the association between the prevalence, awareness, treatment and control rate of hypertension and the potential risk factors.ParticipantsThe sample comprised 2228 Ngawa Tibetan residents (age 18–80 years) from September 2018 to June 2019.ResultsThe prevalence rate of hypertension was 24.6%. The control rate was 6.2%, while the awareness rate (32.3%) and treatment rate (21.7%) of hypertension had been significantly improved.ConclusionThe prevalence of hypertension among Ngawa Tibetans was high. The awareness and treatment were improved in recent years. But the control rate was low. The government needs to strengthen the basic medical care and health education for Ngawa Tibetans.
Hordeum jubatum is a halophyte ornamental plant wildly distributed in the Northeast of China, where the low water potential induced by various abiotic stresses is a major factor limiting plant growth ...and development. However, little is known about the comparative effects of salt, alkali, and drought stresses at uniform water potential on the plants. In the present study, the growth, gas exchange parameters, photosynthetic pigments, and chlorophyll fluorescence in the seedlings of
H. jubatum
under three low water potentials were measured. The results showed that the growth and photosynthetic parameters under these stresses were all decreased except for carotenoid (Car) with the increasing of stress concentration, and alkali stress caused the most damaging effects on the seedlings. The decreased net photosynthetic rate (
P
n), stomatal conductance (
G
s), and intercellular CO
2
concentrations (
C
i) values under salt stress were mainly attributed to stomatal factors, while non-stomatal factors were dominate under drought and alkali stresses. The reduced chlorophyll and slightly increased Car contents occurred under these stresses, and most significant changed under alkali stress. In addition, the maximum photochemical efficiency (Fv/Fm), actual photochemical efficiency (ΦPSII), and photochemical quenching coefficient (q
P
) under the stresses were all decreased, indicating that salt, alkali, and drought stresses all increased susceptibility of PSII to photoinhibition, reduced the photosynthetic activity by the declined absorption of light for photochemistry, and increased PSII active reaction centers. Moreover, the non-photochemical quenching coefficient (NPQ) of alkali stress was different from salt and drought stresses, showing that the high pH of alkali stress caused more damaging effects on the photoprotection mechanism depending on the xanthophyll cycle. The above results suggest that the
H. jubatum
has stronger tolerance of salt than drought and alkali stresses, and the negative effects of alkali stress on the growth and photosynthetic performance of this species was most serious.
This study reports the digestibility and nutritional quality of pasta made from durum wheat semolina which was partially substituted by puree, juice or pomace from spinach and red cabbage. The ...results show that 10% substitution of semolina with red cabbage pomace and spinach pomace, 1% substitution of spinach juice, and 2% substitution of spinach puree significantly reduced the area under the curve of the in vitro starch digestion. This reduction was due to a combined effect of decreased starch content, increased dietary fibre content and inhibition of α-amylase caused by vegetable material addition. Total phenolic content (TPC) and antioxidant capacity increased significantly on raw, cooked and digested samples of vegetable fortified pasta compared to control. The β-carotene content of spinach pasta (raw, cooked, and digested) was also higher than that of control. At the 1% substitution level, the juice was more efficient in improving the antioxidant capacity of resultant pasta compared to puree or pomace.
Abstract
Purpose: With the increasing application of artificial neural network technology in medical diagnosis and health risk prediction, the model of sports medicine integration based on ANNs ...health risk prediction will provide an operable new idea for the development of sports medicine integration in China. Method: This study takes the more common atherosclerosis as an example and uses the artificial neural network analysis technology to predict the disease risk of 1109 patients, explores the effect of physical activity in predicting models, and explores new ideas for the integration of sports and medicine. Results: The model based on the LSTM network has a good predictive effect in realizing the level of physical activity and the risk of atherosclerosis. Therefore, it is recommended to include indicators such as physical activity level and exercise habits to predict and manage disease risks in the development of the integration of sports and medicine.
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