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Sepsis-induced mitochondrial dysfunction:A narrative review

World Journal of Critical Care Medicine 2023年第3期12卷 139-152页

作者： Wagner Nedel Caroline Deutschendorf Luis Valmor Cruz Portela Intensive Care unit Grupo Hospitalar ConceiçãoPorto Alegre 91350200Brazil Laboratory of neurotrauma and Biomarkers Departamento de BioquímicaICBSUniversidade Federal do Rio Grande do SulPorto Alegre 90035-003Brazil Brazilian Research in Intensive Care Network-BRICNet São Paulo 04039-002Brazil Infection Control Committee Hospital de Clínicas de Porto AlegrePorto Alegre 90410-000Brazil

Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic *** function has been shown to be severely impaired during the early phase of critical illness,with a reduction in biogenesis,increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%.Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays,particularly in peripheral mononuclear *** of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection,sample processing,and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear *** have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic ***,few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical *** improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic *** features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care *** evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients,especially those with *** this article,we explore the pathophysiological aspects,main methods of measurement,and the main studies in this field.

关键词： Sepsis Mitochondria Mitochondrial dysfunction Oxidative phosphorylation Inflammation Respirometry

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Protective Effects of Calpain Inhibition on Neurovascular unit Injury through Downregulating Nuclear Factor-KB- related Inflammation during Traumatic Brain Injury in Mice

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Chinese Medical Journal 2017年第2期130卷 187-198页

作者： Xiao-Gang Tao Jing-Hua Shi Shu-Yu Hao Xue-Tao Chen Bai-Yun Liu Department of Neurosurgery Beijing Tian Tan Hospital Capital Medical University Beijing 100050 China Department of Otolaryngology Beijing Tian Tan Hospital Capital Medical University Beijing 100050 China Department of neurotrauma Beijing Neurosurgical Institute Capital Medical University Beijing 100050 China

Background： In addition to neurons, all components of the neurovascular unit （NVU）, such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury （TBI）. Previous studies have shown that excessive stimulation ofcalpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact （CCI）. Methods： One hundred and eight mice were divided into three groups： the sham group, the control group, and the MDL28170 group. MDL28170 （20 mg/kg）, an efficient calpain inhibitor, was administered intraperitoneally at 5 rain, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood-brain barrier （BBB） disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI. Results： The MDL28170 treatment significantly reduced the extent of both cerebral contusion （MDL28170 vs. vehicle group, 16.90 ± 1.01 mm3 and 17.20±1.17 mm3 vs. 9.30 ± 1.05 mm^3 and 9.90 ± 1.17 mm3, both P 〈 0.001 ） and edema （M DL28170 vs. vehicle group, 80.76 ± 1.25% and 82.00 ± 1.84% vs. 82.55 ± 1.32% and 83.64 ± 1.25%, both P 〈 0.05）, improved neurological scores （MDL28170 vs. vehicle group, 7.50 ±0.45 and 6.33 ±0.38 vs. 12.33 ± 0.48 and 11.67±0.48, both P 〈 0.001）, and attenuated NVU damage resulting （including tight junction （TJ）, basement membrane, BBB, and neuron） from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-κB-related inflammation （tumor necrosis factor-α [TNF-α]： MDL28170 vs. vehicle group, 1.15 ± 0.07 and 1.62± 0.08 vs. 1.59±0.10 and 2.18± 0.10, both P 〈 0.001 ： inducible nitric oxide synthase： M DL28170 vs. vehicle group, 4.51± 0.23 vs. 6.23± 0.12, P 〈 0.001 at 24 h; intracellular adhesion molecule- I ： MDL28170 vs. vehicle group, 1.45± 0.13 vs. 1.70 ± 0.12, P

关键词： Calpain Inflammation: Neurovascular unit: Nuclear Factor-κB Traumatic Brain Injury

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Neuroprotective effects of bloodletting at Jing points combined with mild induced hypothermia in acute severe traumatic brain injury

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Neural Regeneration Research 2016年第6期11卷 931-936页

作者： Yue Tu Xiao-mei Miao Tai-long Yi Xu-yi Chen Hong-tao Sun Shi-xiang Cheng Sai Zhang Tianjin Key Laboratory of neurotrauma Repair Institute of Traumatic Brain Injury & Neuroscience of Chinese People's Armed Police ForcesNeurosurgery & Neurology Hospital Affiliated Hospital of Logistics University of Chinese People's Armed Police Forces Graduate School Tianjin University of Traditional Chinese Medicine

Bloodletting at Jing points has been used to treat coma in traditional Chinese medicine. Mild induced hypothermia has also been shown to have neuroprotective effects. However, the therapeutic effects of bloodletting at Jing points and mild induced hypothermia alone are limited. Therefore, we investigated whether combined treatment might have clinical effectiveness for the treatment of acute severe traumatic brain injury. Using a rat model of traumatic brain injury, combined treatment substantially alleviated cerebral edema and bloodbrain barrier dysfunction. Furthermore, neurological function was ameliorated, and cellular necrosis and the inflammatory response were lessened. These findings suggest that the combined effects of bloodletting at Jing points（20 μL, twice a day, for 2 days） and mild induced hypothermia（6 hours） are better than their individual effects alone. Their combined application may have marked neuroprotective effects in the clinical treatment of acute severe traumatic brain injury.

关键词： traumatic alone edema neurological minutes hematoma hematoxylin olfactory neuronal twice

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A tissue-engineered rostral migratory stream for directed neuronal replacement

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Neural Regeneration Research 2018年第8期13卷 1327-1331页

作者： John C.O'Donnell Kritika S.Katiyar Kate V.Panzer D.Kacy Cullen Center for Brain Injury & Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania Center for neurotrauma Neurodegeneration & Restoration Corporal Michael Crescenz Veterans Affairs Medical Center School of Biomedical Engineering Drexel University Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania

New neurons are integrated into the circuitry of the olfactory bulb throughout the lifespan in the mamma- lian brain--including in humans. These new neurons are born in the subventricular zone and subsequently mature as they are guided over long distances via the rostral migratory stream through mechanisms we are only just beginning to understand. Regeneration after brain injury is very limited, and although some neuroblasts from the rostral migratory stream will leave the path and migrate toward cortical lesion sites, this neuronal replacement is generally not sustained and therefore does not provide enough new neurons to alleviate functional deficits. Using newly discovered microtissue engineering techniques, we have built the first self-contained, implantable constructs that mimic the architecture and function of the rostral migratory stream. This engineered microtissue emulates the dense cord-like bundles of astrocytic somata and processes that are the hallmark anatomical feature of the glial tube. As such, our living microtissue-en- gineered rostral migratory stream can serve as an in vitro test bed for unlocking the secrets of neuroblast migration and maturation, and may potentially serve as a living transplantable construct derived from a patient＇s own cells that can redirect their own neuroblasts into lesion sites for sustained neuronal replace- ment following brain injury or neurodegenerative disease. In this paper, we summarize the development of fabrication methods for this microtissue-engineered rostral migratory stream and provide proof-of-princi- ple evidence that it promotes and directs migration of immature neurons.

关键词： rostral migratory stream glial tube astrocyte neuroblast brain injury neural repair neural regeneration tissue engineering

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The role of poly-L-ornithine in determining neural stem cell fate

The role of poly-L-ornithine in determining neural stem cell...

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第十四届中国医师协会神经外科医师年会

作者： Kaiyuan Zhang Hua Feng Department of Neurosurgery and Key Laboratory of neurotrauma Southwest HospitalThird Military Medical University

The most attractive strategies to restore an injured brain are cell replacement therapies or stimulation of endogenous stem cells to date. Biomaterial-supported culture methods provide possibilities to investigate the characteristics of neural stem/progenitor cells（NSPCs） in vitro. In this study, we evaluate the suitability of three different substrates（poly-L-lysine, poly-L-ornithine and fibronectin） on the proliferation and differentiation towards young neurons of NSPCs in vitro. Immunocytochemistry analyses showed that cells grown on poly-L-ornithine（PO） present increased proliferation and differentiation toward neural lineages with respect to poly-L-lysine（PLL） control and to fibronectin（Fn） group. Westren Blot analyses confirmed these results by the expression of marker of neuronal subtype. These effects were significantly inhibited with the addition of U0126（an ERK antagonist） and enhanced with addition of Ceramide C6（an ERK agonist）. Our data indicate that poly-L-ornithine might serve as a suitable biomaterial to promote proliferation and enhance neuronal specification of NSPCs in vitro and ERK signalling pathway plays a pivotal role during this process.

关键词： neural stem/progenitor cells poly-L-lysine poly-L-ornithine fibronectin ERK

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The effect of umbrella-type branching on the blood circulation and tumor targeting of star-branched PLA-PMPC copolymer micelles

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Science China(Technological Sciences) 2021年第1期64卷 71-82页

作者： LONG LiXia CHENG LinJie HOU JingJing WANG LiMei WANG Xu HE LiGang LI SiDi ZHAO Jin HOU Xin KANG ChunSheng YUAN XuBo Tianjin Key Laboratory of Composite and Functional Materials School of Materials Science and EngineeringTianjin UniversityTianjin 300072China Department of Neurosurgery Tianjin Medical University General HospitalLab of Neuro-oncologyTianjin Neurological InstituteKey Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous SystemMinistry of Education and Tianjin CityTianjin 300052China

The effect of branching on the blood circulation and tumor targeting of polymer nanovehicles in vivo was investigated in this study. For the purpose, star-branched poly(lactic acid) and poly(2-methacryloyloxyethyl phosphorylcholine)(PLA-PMPC)copolymers with umbrella-type AB3,(AB3)_(2), and(AB3)_(3) architecture were synthesized by branching at the PLA core. Micelles self-assembled from these copolymers were used to evaluate the effect of core branching on blood circulation and tumor targeting. The results showed that branching changed the behavior of polymeric self-assembly in solution, thereby changing the size and surface anti-fouling performance of the polymeric micelles. Moreover, star-branched copolymer micelles with a higher branching degree allowed their payload to persist better in blood(half-time prolonged from 7.1, 8.6 to 13.8 h) and for a 1.72-fold higher content at the tumor site. These studies suggest that raising the branching degree of amphiphilic copolymer potentially offers a promising strategy for the design of carriers capable of enhanced circulation and targeting in vivo.

关键词： umbrella-type branching star-branched copolymers anti-fouling prolonged circulation

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Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant α-synuclein

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Neural Regeneration Research 2018年第8期13卷 1375-1383页

作者： Huan-Cheng Wu Qun-Liang Hu Shi-Jun Zhang Yan-Min Wang Zhan-Kui Jin Ling-Fu Lv Sai Zhang Zhen-Lin Liu Hong-Lian Wu Ou-Mei Cheng Graduate School Tianjin Medical University Tianjin China Tianjin Beichen Hospital Tianjin China Tianjin Key Laboratory of neurotrauma Repair Institute of Traumatic Brain Injury and Neuroscience Center for Neurology and Neurosurgery of Affiliated Hospital Logistics University of Chinese People's Armed Police Force Tianjin China Department of Clinical Medicine Chongqing Medical University Chongqing China

Genistein, a potent antioxidant compound, protects dopaminergic neurons in a mouse model of Parkinson＇s disease. However, the mecha- nism underlying this action remains unknown. This study investigated human SH-SYSY cells overexpressing the A53T mutant of α-synuclein. Four groups of cells were assayed： a control group （without any treatment）, a genistein group （incubated with 20 μM genistein）, a rote- none group （treated with 50 μM rotenone）, and a rotenone ＋ genistein group （incubated with 20 μM genistein and then treated with 50μM rotenone）. A lactate dehydrogenase release test confirmed the protective effect of genistein, and genistein remarkably reversed mitochondrial oxidative injury caused by rotenone. Western blot assays showed that BCL-2 and Beclin ! levels were markedly higher in the genistein group than in the rotenone group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed that genistein inhibited rotenone-induced apoptosis in SH-SYSY cells. Compared with the control group, the expression of NFE2L2 and HMOX1 was significantly increased in the genistein ＋ rotenone group. However, after treatment with estrogen receptor and NFE2L2 channel blockers （ICI-182780 and ML385, respectively）, genistein could not elevate NFE2L2 and HMOX1 expression. ICI-182780 effectively prevented genistein-mediated phosphorylation of NFE2L2 and remarkably suppressed phosphorylation of AKT, a protein downstream of the estrogen receptor. These findings confirm that genistein has neuroprotective effects in a cell model of Parkinson＇s dis- ease. Genistein can reduce oxidative stress damage and cell apoptosis by activating estrogen receptors and NFE2L2 channels.

关键词： nerve regeneration genistein neuroprotection SH-SYSY cells Parkinson's disease rotenone estrogen receptor NFE2L2 A53T a-synuclein oxidative stress neurodegeneration neural regeneration

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Magnetic resonance imaging-three-dimensional printing technology fabricates customized scaffolds for brain tissue engineering

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Neural Regeneration Research 2017年第4期12卷 614-622页

作者： Feng Fu Zhe Qin Chao Xu Xu-yi Chen Rui-xin Li Li-na Wang Ding-wei Peng Hong-tao Sun Yue Tu Chong Chen Sai Zhang Ming-liang Zhao Xiao-hong Li Institute of Traumatic Brain Injury and Neurology Pingjin Hospital Logistics University of Chinese People's Armed Police Forces Tianjin China Key Laboratory of neurotrauma Repair ofTianjin Tianjin China Pingjin Hospital Logistics University of Chinese People's Armed Police Forces Tianjin China Institute of Medical Equipment The Academy of Military Medical Sciences Tianjin China

Conventional fabrication methods lack the ability to control both macro- and micro-structures of generated scaffolds. Three-dimensional printing is a solid free-form fabrication method that provides novel ways to create customized scaffolds with high precision and accuracy. In this study, an electrically controlled cortical impactor was used to induce randomized brain tissue defects. The overall shape of scaffolds was designed using rat-specific anatomical data obtained from magnetic resonance imaging, and the internal structure was created by computer- aided design. As the result of limitations arising from insufficient resolution of the manufacturing process, we magnified the size of the cavity model prototype five-fold to successfully fabricate customized collagen-chitosan scaffolds using three-dimensional printing. Results demonstrated that scaffolds have three-dimensional porous structures, high porosity, highly specific surface areas, pore connectivity and good internal characteristics. Neural stem cells co-cultured with scaffolds showed good viability, indicating good biocompatibility and biodegradability. This technique may be a promising new strategy for regenerating complex damaged brain tissues, and helps pave the way toward personalized medicine.

关键词： nerve regeneration three-dimensional printing traumatic brain injury tissue engineering scaffolds magnetic resonance imaging collagen chitosan mimics neural regeneration

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G Protein-Coupled Estrogen Receptor 1 Negatively Regulates the Proliferation of Mouse-Derived Neural Stem/Progenitor Cells via Extracellular Signal-regulated Kinase Pathway

G Protein-Coupled Estrogen Receptor 1 Negatively Regulates t...

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第十四届中国医师协会神经外科医师年会

作者： Jun Zhong Hong-fei Ge Chao Zhang Jing-yu Chen Huan-huan Li Xuan-yu Fang Liang Tan Xin Liu Zheng-cai Jia Hua Feng Rong Hu Department of Neurosurgery and Key Laboratory of neurotrauma Southwest HospitalThird Military Medical University （Army Medical university）

G protein-coupled estrogen receptor 1（GPER1, also known as GPR30） has been reported to play a wide range of function in the central nervous system（CNS）. However, whether GPER1 is expressed by neural stem/progenitor cells（NSPCs） and its role has not been established. Here, we found the expression of GPER1 in mouse-derived NSPCs via western blot and immunofluorescent staining. Moreover, we revealed that specific activation of GPER1 by the agonist G1 decreased the proliferation of NSPCs in a dose-dependent manner. The neurosphere formation assay and Ki67 staining further demonstrated that activation of GPER1 inhibited the proliferation of NSPCs. Additionally, the inhibitory effect of G1 on the proliferation of NSPCs could be blocked by the specific GPER1 antagonist G15. Intriguingly, ERK pathway was involved in the negative effect of GPER1 on the proliferation of NSPCs, because the phosphorylation level of ERK in NSPCs was remarkably decreased during G1 treatment. However, the antagonist G15 reversed the down-regulated level of p-ERK. Knock-down GPER1 also reversed the inhibitory effect of G1 on NSPCs proliferation. Together, our results provide the first evidence that GPER1 is expressed by NSPCs and its activation negatively modulates the proliferation of NSPCs, highlighting the importance of GPER1 in regulating NSPC behaviors.

关键词： Neural stem/progenitor cells G protein-coupled estrogen receptor 1 Proliferation Extracellular signal-regulated kinase

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Terahertz two-pixel imaging based on complementary compressive sensing

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Chinese Physics B 2018年第11期27卷 487-493页

作者：王与烨任宇琛陈霖宇宋词李长昭张超徐德刚姚建铨 Institute of Laser and Optoelectronics School of Precision Instrument and Optoelectronics Engineering Tianjin University Tianjin 300072 China Key Laboratory of Optoelectronic Information Science and Technology (Ministry of Education) Tianjin University Tianjin 300072 China Department of Neurosurgery and Key Laboratory of neurotrauma Southwest Hospital Third Military Medical University (Army Medical University) Chongqing 400038 China College of Computer and Information Engineering Tianjin Agricultural University Tianfin 300384 China

A compact terahertz（THz） imaging system based on complementary compressive sensing has been proposed using two single-pixel detectors. By using a mechanical spatial light modulator, sampling in the transmission and reflection orientations was achieved simultaneously, which allows imaging with negative mask values. The improvement of THz image quality and anti-noise performance has been verified experimentally compared with the traditional reconstructed image, and is in good agreement with the numerical simulation. The demonstrated imaging system, with the advantages of high imaging quality and strong anti-noise property, opens up possibilities for new applications in the THz region.

关键词： terahertz imaging image reconstruction techniques spatial light modulators

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