Aging and Disease
·
2024
·Vol. 16
·期 5
·3069
·
IF 7
Yiran Huang,Nan Gao,Boren Liu,Weili Luo,Jianfei Chen,Yan Chen,Yong Bi,Zikai Zhou
Adult hippocampal neurogenesis (AHN) is crucial to various brain functions. Neurodegeneration, neuroinflammation and stress can impair AHN, contributing to the development of neurological and psychiatric disorders. Stress is known to extensively affect both the brain and peripheral immune system. However, the cellular and molecular mechanisms underlying stress-induced impairments in AHN remain unclear. In this study, we found that, unlike neuroinflammatory conditions, stress significantly inhibited AHN independently of microglial activation, suggesting a novel mechanism mediating stress-impaired AHN. Since stress modulates peripheral immune cells, we examined the distribution of immune cells infiltrating the brain. We found a significant decrease of infiltrated Ly6C hi monocytes in the brain parenchyma. In the blood, adoptively transferred ZsGreen + Ly6C hi monocytes drastically reduced due to stress-induced homing to the bone marrow. Adrenalectomy (ADX) experiments revealed that monocyte homing is regulated by glucocorticoid and may cause impairments in AHN. Depleting peripheral circulating monocytes reduced brain-resident Ly6C hi monocytes and replicated the stress-induced inhibition of AHN, independent of microglia activation. RNA sequencing analysis of Ly6C hi monocytes revealed a stress-induced transcriptional profile, suggesting their supportive role in neuronal functions. Together, these findings demonstrate a novel and essential role of brain resident Ly6C hi monocytes in maintaining AHN at basal level, which is important for brain functions.
研究领域:
神经科学
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免疫学
·
分子生物学
·
神经免疫学
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应激生物学
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干细胞生物学
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转化医学
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DOI
PubMed
高影响因子
Aging and Disease
·
2024
·
IF 7
Li Li,Paul R. Krafft,Na Zeng,Ranran Duan,Xiang Qi,Anwen Shao,Fushan Xue,John H. Zhang
Ischemic stroke can be a serious complication of selective carotid endarterectomy (CEA) in patients with carotid artery stenosis (CAS). The underlying risk factors and mechanisms of these postoperative strokes are not completely understood. Our previous study showed that TMEM166-induced neuronal autophagy is involved in the development of secondary brain injury following cerebral ischemia-reperfusion injury in rats. This current study aimed to investigate the role of TMEM166 in ischemic stroke following CEA. In the clinical part of this study, the quantitative analysis demonstrated circulating TMEM166, interleukin 6 (IL-6), and C-reactive protein (CRP) levels were significantly elevated in patients who suffered an ischemic stroke after CEA compared to those who did not. Furthermore, non-survivors exhibited higher levels of these proteins than survivors. In the preclinical part of this study, a middle cerebral artery occlusion (MCAO) model was implemented following CAS simulation in TMEM166 -/- mice. We found TMEM166 expression was positively correlated with the degree of ischemic brain injury. Ad5-TMEM166 transfection aggravated ischemic brain injury by inducing microglial autophagy activation and release of inflammatory cytokines. Accordingly, TMEM166 deficiency reduced brain inflammation and inhibited excessive microglial autophagy through the mammalian target of rapamycin (mTOR) pathway. These findings suggest that TMEM166 may play a key role in the development of ischemic injury after CEA and may serve as a biomarker for risk assessment of postoperative ischemic stroke.
研究领域:
神经科学
·
心血管疾病
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Aging and Disease
·
2024
·Vol. 16
·期 3
·1652
·
IF 7
Cheng Zhuang,Ruiqi Sun,Yuchen Zhang,Qing Zou,Jianxin Zhou,Naijun Dong,Xuyu Zhao,Wenjun Fu,Xiaoke Geng,Jiao Wang,Qian Li,Robert Chunhua Zhao
Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.
研究领域:
纳米医学
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免疫学
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药理学
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细胞生物学
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生物医学工程
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风湿病学
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DOI
PubMed
高影响因子
Aging and Disease
·
2023
·
IF 7.4
Guoxiang Liu,Xiaoxia Li,Fanghao Yang,Jingyu Qi,Lipeng Shang,Huhu Zhang,Shuang Li,Fenghua Xu,Lingne Li,Huaxin Yu,Yang Li,Xiaolei Dong,Qinghang Song,Feng Zhu,Guang Chen,Can Cao,Liangqian Jiang,Junzhe Su,Lina Yang,Xiaohui Xu,Zhe Zhang,Robert Chunhua Zhao,Bing Li
The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.
研究领域:
干细胞生物学
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衰老研究
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Kateřina Veverová,Jan Laczó,Alžběta Katonová,Hana Horáková,Veronika Matušková,Francesco Angelucci,Martina Laczó,Zuzana Nedelská,Jakub Hort,He-Ling Wang,Jianying Zhang,Liu Shi,Evandro Fei Fang,Martin Vyhnálek
Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.
研究领域:
神经病学
·
神经退行性疾病
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生物标志物研究
·
临床神经科学
✓ 已验证
DOI
高影响因子
KOREAN JOURNAL OF CHEMICAL ENGINEERING
·
2026
·
IF 3.4
Dai Yanmei,Teng Jiayu,Zhang Qingyu,Sun Dongchang,Tao Zijuan,Huang Changshun,Luo Liangli,Liu Bo,Ou Zhimin
9α-Hydroxyandrost-4-ene-3,17-dione (9α-OH-AD) is a valuable intermediate for the manufacture of steroid drugs such as hydrocortisone. Its bioproduction from 4-androstene-3,17-dione (4-AD), however, is limited by the low efficiency of the two-component steroid 9α-hydroxylase (KSH) system and insufficient cofactor regeneration during whole-cell catalysis. In this work, RvKshA and RvKshB were mined and heterologously expressed, and plasmid screening identified E. coli BL21/pET28a + -RvKshA/pETDuet-1-RvKshB as the best-performing strain. Structural analyses based on molecular docking and molecular dynamics simulations clarified the cooperative catalytic mechanism of KshA and KshB, providing guidance for rational system construction. More importantly, to address the NADH supply bottleneck, we established a dual-enzyme coupling strategy by introducing formate dehydrogenase (FDH) for in situ cofactor regeneration. This design enabled efficient steroid hydroxylation, giving a 98.3% conversion at 20 mM 4-AD. When combined with high-density fermentation and fed-batch feeding, the engineered strain achieved a substrate processing capacity of 80 mM and a spatiotemporal yield of 42.8 mM/(L·day). This study provides an integrated enzymatic and bioprocess solution for improving whole-cell steroid hydroxylation efficiency and offers a practical basis for the scalable biosynthesis of 9α-OH-AD.
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DOI
高影响因子
Membranes
·
2023
·Vol. 13
·期 7
·665
·
IF 4.2
Jie Li,Ting He,Hongyu Chen,Yangming Cheng,Enrico Drioli,Zhaohui Wang,Zhaoliang Cui
HighlightsPreparation of anti-wetting polypropylene membrane using environmentally friendly diluents via TIPS methodOptimization of Preparation Process for Polypropylene Hollow Fiber MembraneFluorinated polymer modified membrane enhances anti-wetting performance and blood compatibilityAbstractA high-performance polypropylene hollow fiber membrane (PP-HFM) was prepared by using a binary environmentally friendly solvent of polypropylene as the raw material, adopting the thermally induced phase separation (TIPS) method, and adjusting the raw material ratio. The binary diluents were soybean oil (SO) and acetyl tributyl citrate (ATBC). The suitable SO/ATBC ratio of 7/3 was based on the size change of the L-L phase separation region in PP-SO/ATBC thermodynamic phase diagram. Through the characterization and comparison of the basic performance of PP-HFMs, it was found that with the increase of the diluent content in the raw materials, the micropores of outer surface of the PP-HFM became larger, and the cross section showed a sponge-like pore structure. The fluoropolymer, Hyflon ADx, was deposited on the outer surface of the hollow fiber membrane using a physical modification method of solution dipping. After modification, the surface pore size of the Hyflon AD40L modified membranes decreased; the contact angle increased to around 107°; the surface energy decreased to 17 mN·m−1; and the surface roughness decreased to 17 nm. Hyflon AD40L/PP-HFMs also had more water resistance properties from the variation of wetting curve. For biocompatibility of the membrane, the adsorption capacity of the modified PP membrane for albumin decreased from approximately 1.2 mg·cm−2to 1.0 mg·cm−2, and the adsorption of platelets decreased under fluorescence microscopy. The decrease in blood cells and protein adsorption in the blood prolonged the clotting time. In addition, the hemolysis rate of modified PP membrane was reduced to within the standard of 5%, and the cell survival rate of its precipitate was above 100%, which also indicated the excellent biocompatibility of fluoropolymer modified membrane. The improvement of hydrophobicity and blood compatibility makes Hyflon AD/PP-HFMs have the potential for application in membrane oxygenators.Keywords:polypropylene;thermally induced phase separation;environmentally friendly diluent;fluoropolymer;ECMO
研究领域:
材料科学
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生物医学工程
·
膜技术
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产品关联
DOI
PubMed
高影响因子
BIOFACTORS
·
2021
·Vol. 47
·期 4
·587-599
·
IF 6.113
Ninghua Wu,Wu Liu,Jiawen Wang,Yanqi Han,Yu Ye,Xiufen Liu,Yuandong Yu,Qingjie Chen,Yongfen Bao,Chao Liu
IR (insulin resistance) in diabetic brain gave rise to the generation of toxic factor Aβ42 and axon collapse which were the marker of AD (Alzheimer's disease)-like lesions in the circumstance of diabetes mellitus. But the underling molecular mechanism was not clear. Chronic HGHI (high glucose and high insulin) exposure accelerates IR has been reported in type II diabetes models. Berberine has been shown to promising effect for IR in vitro and in vivo. This study demonstrates the protective effect and the underlying mechanism of berberine on HGHI-induced IR. HGHI-induced cells were used to mimic the hyperinsulinemia resulting in IR. Berberine was used to uncover the mechanisms for the treatment of hyperinsulinemia in IR model. Morris water maze (MWM), PET imaging, CCK8 assay, ELISA assay, glucose kits, microscopy, and western blot analysis were performed to evaluate the protective effects of berberine. Berberine-improved HGHI-induced IR was correlated with the increase of glucose application in neurons. Meanwhile, the expressions of Pi3K, as well as GLUT3, PKCε, and APP were downregulated in the model, while p-IRS Ser307 was upregulated compared with Normal group. Fortunately, these scenes were reversed by berberine administration. Furthermore, berberine decreased GSK3β Y216 expressions, inhibited the production of oligomer Aβ42 and extended neuronal axon. The monomeric berberine treatment improves IR that may be involved in glucose effective application, rectifying the related proteins of the aberrant insulin pathway. Additionally, it suppressed the generation of Aβ42 and ameliorated neuron axon damage. Finally, berberine improves DM (diabetes mellitus)-induced cognitive impairment.
研究领域:
药理学
·
神经科学
·
糖尿病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Coatings
·
2019
·Vol. 9
·期 7
·421
·
IF 2.33
Lei Peng,Musong Lin,Sheng Zhang,Li Li,Qiang Fu,Junbo Hou
A self-healing coating with UV-shielding property was prepared in this paper. The self-healing property was based on the inclusion between a host (β-CD-TiO2) and a guest HEMA-Ad). After inclusion of the host and guest, the host–guest complex (HEMA-Ad/β-CD-TiO2) was polymerized with other reactive monomers (HEMA and BA) to obtain the final coating. The coating had good hydrophobicity (water contact angle >90°, moisture absorption rate <2%) and excellent UV-shielding performance (ultra-violet protect factor >90%), and could be firmly bonded to a soft substrate. In addition, the coating had good self-healing property, which means that cracks in the material can recover many times after being damaged and that the UV-shielding ability can be fully restored with the self-healing process.Keywords:coating;self-healing;UV-shielding;host–guest
研究领域:
材料科学
·
化学工程
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DOI
高影响因子
CHIRALITY
·
2018
·Vol. 30
·期 12
·1245-1256
·
IF 1.833
Jiawei Ding,Ming Zhang,Huixue Dai,Chunmian Lin
Mandelic acid and its derivatives are important chiral analogs which are widely used in the pharmaceutical synthetic industry. The present study investigated the enantiomeric separation of six mandelic acids (mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-chloromandelic acid, 4-bromomandelic acid, 4-methoxymandelic acid) on the Chiralpak AD-3 column by supercritical fluid chromatography. The influences of volume fraction of trifluoroacetic acid, type and percentage of modifier, column temperature, and backpressure on the separation efficiency were investigated. And the enantiomer elution order was determined. The results show that, for a given modifier, the retention factor, the separation factor, and the separation resolution decreased gradually with increasing the volume ratio of the modifier. At the same volume ratio of modifier, the retention factor of the mandelic acid and its derivatives increased in the order of methanol, ethanol, and isopropanol, except 3-chloromandelic acid. The separation factor and the separation resolution decreased with the increase of column temperature (below the temperature limit). The backpressure affected the enantioseparation process: As the backpressure increased, a corresponding decrease in retention factor was observed. Under the same chiral column conditions, the SFC method exhibited faster and more efficient separation with better enantioselectivity than the HPLC method.
研究领域:
分析化学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2024
·Vol. 103
·期 4
·e14529
·
IF 3.2
Aihong Yang,Xiaoyue Yi,Hongwei Zhang,Rui Shen,Xiaodi Kou
With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives ( 1 – 4 ) were designed, synthesized, and characterized by 1 H NMR, 13 C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that 1–4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu 2+ ions), antioxidation, self-induced, Cu 2+ -induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood–brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10 −8 M magnitude) and BuChE (10 −7 M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.
研究领域:
药物化学
·
神经科学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
Phytochemistry Letters
·
2019
·
IF 1.338
Jun Wang,Cai-Hong Li,Mahdi Moridi Farimani,Jun-Li Yang
To search for potential candidate anti-AD agents, the gypenosideson the aerial parts of Gynostemma pentaphyllum were phytochemically investigated, yielding two undescribed ( 1 - 2 ) and five known ( 3 - 7 ) dammarane saponins. Their molecular structures were unambiguously elucidated via spectroscopic analyses (1D and 2D NMR, HR-ESI-MS, IR, and optical rotation) chemical transformations. All of the compounds possessed a 21- O - n -butyl-20,21-dihydroxy-21,23-epoxydammar-24-ene moiety in their structures. The short-term memory assay on a transgenic fly Alzheimer’s disease (AD) model revealed that all of the compounds displayed potential anti-AD activity. Of the compounds, 1 and 6 at 10 μM showed comparable short-term memory rescue ability to memantine, the positive control, at 100 μM. This study revealed the potent antagonistic effect of dammarane-type saponins 1 and 6 against Alzheimer’s disease.
研究领域:
植物化学
·
神经科学
·
药物开发
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DOI
高影响因子
危险品化学品经营许可证（带存储）