Search

Introduction: The etiology of Parkinson's disease (PD) is still unknown. Until now, oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. However, the specific synergistic role of oxidative stress and neuroinflammation in the occurrence and development of PD remains unclear., Methods: The changes in motor behavior, dopamine (DA) neurons quantification and their mitochondrial respiratory chain, glial cells activation and secreted cytokines, Nrf2 signaling pathway, and redox balance in the brain of rats were evaluated., Results: Lipopolysaccharide (LPS)-induced neuroinflammation and rotenone (ROT)-induced oxidative stress synergistically aggravated motor dysfunction, DA neuron damage, activation of glial cells, and release of related mediators, activation of Nrf2 signaling and destruction of oxidative balance. In addition, further studies indicated that after ROT-induced oxidative stress caused direct damage to DA neurons, LPS-induced inflammatory effects had stronger promoting neurotoxic effects on the above aspects., Conclusions: Neuroinflammation and oxidative stress synergistically aggravated DA neuronal loss. Furtherly, oxidative stress followed by neuroinflammation caused more DA neuronal loss than neuroinflammation followed by oxidative stress., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Cytochrome P450 26A1 (CYP26A1) plays a vital role in early pregnancy in mice. Our previous studies have found that CYP26A1 affects embryo implantation by modulating natural killer (NK) cells, and that there is a novel population of CYP26A1 + NK cells in the uteri of pregnant mice. The aim of this study was to investigate the effects of CYP26A1 on the subsets and killing activity of NK cells. Through single-cell RNA sequencing (scRNA-seq), we identified four NK cell subsets in the uterus, namely, conventional NK (cNK), tissue-resident NK (trNK) 1 and 2, and proliferating trNK (trNKp). The two most variable subpopulations after uterine knockdown of CYP26A1 were trNKp and trNK2 cells. CYP26A1 knockdown significantly downregulated the expression of the NK cell function-related genes Cd44, Cd160, Vegfc, and Slamf6 in trNK2 cells, and Klra17 and Ogn in trNKp cells. Both RNA-seq and cytotoxicity assays confirmed that CYP26A1 + NK cells had low cytotoxicity. These results indicate that CYP26A1 may affect the immune microenvironment at the maternal-foetal interface by regulating the activity of NK cells., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is one of the most common central nervous system (CNS) degenerative disease and is characterized by a progressive loss of midbrain substantia nigra dopamine (DA) neurons. Dendrobium nobileLindl alkaloid (DNLA) is an active component extracted from D. nobile Lindl, which is a traditional Chinese herb. The various pharmacological effects of D. nobile are beneficial for human health. Recently, DNLA-mediated neuroprotective effects have been reported. However, the neuroprotection of DNLA on 6-hydroxydopamine (6-OHDA)-induced DA neurotoxicity is still unknown. This study aimed to explore the neuroprotective effects of DNLA on DA neurotoxicity induced by 6-OHDA. In PD rat model, continuous intragastric administration of DNLA (20 mg/kg) for 7 days significantly ameliorated 6-OHDA-induced DA neurons loss in the midbrain substantia nigra. In addition, primary rat midbrain neuron-glia cocultures were used to explore the mechanisms underlying DNLA-related DA neuroprotection. The studies on neuron-glia cocultures revealed that neuroprotective effects of DNLA (2.5 ng/mL) were mediated by inhibiting the release of proinflammatory cytokines. Taken together, DNLA holds neuroprotective effect on 6-OHDA-induced neurons neurodegeneration by selectively inhibiting the production of proinflammatory factors and could be a potential compound for PD treatment., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)

Cyp26a1 had important roles in mouse embryo implantation and was highly expressed in some of NK cells at the human maternal-foetal interface in early pregnancy. However, the regulatory effect of Cyp26a1 on NK cells remains poorly understood. Through qPCR and flow cytometric assays, we found that Cyp26a1 was expressed by mouse uterine NK cells but not spleen NK cells during the peri-implantation period and there was a group of NK cells that highly expressed Cyp26a1, that is Cyp26a1 + NK cell subset. single cell-population transcriptome sequencing on Cyp26a1 + NK and Cyp26a1 - NK cell subsets was performed. We found that there were 3957 differentially expressed genes in the Cyp26a1 + NK cell subset with a cut-off of fold change ≥2 and FDR < 0.01, 2509 genes were up-regulated and 1448 genes were down-regulated in Cyp26a1 + NK cell subset. Moreover, cytokine-cytokine receptor interaction signalling pathway and natural killer cell-mediated cytotoxicity signalling pathway were enriched according to KEGG pathway enrichment analysis. We further found that the expression of Gzma and Klrg1 was significantly increased and Fcgr4 was significantly decreased when inhibiting Cyp26a1. Our experimental results show that there is a novel NK cell subset of Cyp26a1 + NK cells in mouse uterus and Cyp26a1 can regulate the gene expression of Gzma, Klrg1 and Fcgr4 in the Cyp26a1 + NK cells., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Recent studies have demonstrated a marked decrease in peripheral lymphocyte levels in patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few studies have focused on the changes of NK, T- and B-cell subsets, inflammatory cytokines and virus-specific antibodies in patients with moderate COVID-19. A total of 11 RT-PCR-confirmed convalescent patients with COVID-19 and 11 patients with non-SARS-CoV-2 pneumonia (control patients) were enrolled in this study. NK, CD8 + T, CD4 + T, Tfh-like and B-cell subsets were analysed using flow cytometry. Cytokines and SARS-CoV-2-specific antibodies were analysed using an electrochemiluminescence immunoassay. NK cell counts were significantly higher in patients with COVID-19 than in control patients (P = 0.017). Effector memory CD8 + T-cell counts significantly increased in patients with COVID-19 during a convalescent period of 1 week (P = 0.041). TIM-3 + Tfh-like cell and CD226 + Tfh-like cell counts significantly increased (P = 0.027) and decreased (P = 0.022), respectively, during the same period. Moreover, ICOS + Tfh-like cell counts tended to decrease (P = 0.074). No abnormal increase in cytokine levels was observed. The high expression of NK cells is important in innate immune response against SARS-CoV-2. The increase in effector memory CD8 + T-cell counts, the up-regulation of inhibitory molecules and the down-regulation of active molecules on CD4 + T cells and Tfh-like cells in patients with COVID-19 would benefit the maintenance of balanced cellular and humoural immune responses, may prevent the development of severe cases and contribute to the recovery of patients with COVID-19., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. Oxidative stress is one of key contributors to PD. Nuclear factor erythroid-2-related factor 2 (Nrf2) is considered to be a master regulator of many genes involved in anti-oxidant stress to attenuate cell death. Therefore, activation of Nrf2 signalling provides an effective avenue to treat PD. Ellagic acid (EA), a natural polyphenolic contained in fruits and nuts, possesses amounts of pharmacological activities, such as anti-oxidant stress and anti-inflammation. Recent studies have confirmed EA could be used as a neuroprotective agent in neurodegenerative diseases. Here, mice subcutaneous injection of rotenone (ROT)-induced DA neuronal damage was performed to investigate EA-mediated neuroprotection. In addition, adult Nrf2 knockout mice and different cell cultures including MN9D-enciched, MN9D-BV-2 and MN9D-C6 cell co-cultures were applied to explore the underlying mechanisms. Results demonstrated EA conferred neuroprotection against ROT-induced DA neurotoxicity. Activation of Nrf2 signalling was involved in EA-mediated DA neuroprotection, as evidenced by the following observations. First, EA activated Nrf2 signalling in ROT-induced DA neuronal damage. Second, EA generated neuroprotection with the presence of astroglia and silence of Nrf2 in astroglia abolished EA-mediated neuroprotection. Third, EA failed to produce DA neuroprotection in Nrf2 knockout mice. In conclusion, this study identified EA protected against DA neuronal loss via an Nrf2-dependent manner., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Astroglia support neuron by providing substrates for neuronal metabolism, glutamate clearance, and antioxidative protection. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in the antioxidative defense response. Also, Nrf2 signaling is recognized to activate the neurotrophic pathway to replace/protect damaged organelles. Ellagic acid (EA), an extraction component of fruits and nuts, presents many pharmacological activities such as anti-inflammation, antioxidation, and neuroprotection. However, few studies have been focused on the neurotrophic properties of EA. Our study investigated whether EA could increase neuronal survival and the target cells. Thus, primary neuron-enriched cultures and primary astroglia-enriched cultures were applied to detect whether EA-elicited neurotrophic effects were mediated by astroglia Nrf2. This study indicated that EA promoted neuronal survival. Further, astroglia Nrf2 participate in EA-elicited neuronal survival with the following scenarios. First, EA elicited astroglia proliferation, glial cell line-derived neurotrophic factor (GDNF) release, and Nrf2 activation. Second, after silencing astroglia Nrf2, EA-induced astrogliosis, GDNF release, and neuronal survival disappeared. Thus, EA-mediated astroglia Nrf2 activation is important to enhance neurotrophic effects on neurons, which might provide new insights for neurodegenerative disease., (© 2019 International Union of Biochemistry and Molecular Biology, Inc.)

Cytochrome P450 26A1 (CYP26A1) plays important roles in the mice peri-implantation period. Inhibiting its expression or function leads to pregnancy failure. However, little is known about the underlying mechanisms involved, especially the relationship between CYP26A1 and immune cells. In this study, using Cyp26a1-specific antisense morpholigos (Cyp26a1-MO) knockdown mice model and pCR3.1-Cyp26a1 vaccine mice model, we found that the number of uterine CD45 + CD11c + MHCII lo-hi F4/80 - dendritic cells (DCs) was significantly decreased in the treated mice. The percentage of mature DCs (CD86 hi ) was obviously lower and the percentage of immature DCs (CD86 lo ) was remarkably higher in uterine DCs in the treatment group than that of the control group. Further experiments found that ID2, a transcription factor associated with DCs development, and CD86, a DC mature marker molecule, were both significantly reduced in mice uteri in the treated group. In vitro, ID2 and CD86 also decreased in bone marrow-derived DCs under Cyp26a1-MO treatment. These findings provide novel information that CYP26A1 might affect the embryo implantation via modulating the differentiation and maturation of uterine DCs., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Cytochrome P450 26A1 (CYP26A1) has a spatiotemporal expression pattern in the uterus, with a significant increase in mRNA and protein levels during peri-implantation. Inhibiting the function or expression of CYP26A1 can cause pregnancy failure, suggesting an important regulatory role of CYP26A1 in the maintenance of pregnancy. However, little is known about the exact mechanism involved. In this study, using a pCR3.1-cyp26a1 plasmid immunization mouse model and a Cyp26a1-MO (Cyp26a1-specific antisense oligos) knockdown mouse model, we report that the number of Dolichos biflorus agglutinin (DBA) lectin-positive uterine natural killer (uNK) cells was reduced in pCR3.1-cyp26a1 plasmid immunized and Cyp26a1-MO-treated mice. In contrast, the percentage of CD3 - CD49b + NK cells in the uteri from the treatment group was significantly higher than that of the control group in both models. Similarly, significantly up-regulated expression of CD49b (a pan-NK cell marker), interferon gamma, CCL2, CCR2 (CCL2 receptor) and CCL3 were detected in the uteri of pCR3.1-cyp26a1- and Cyp26a1-MO-treated mice. Transcriptome analysis suggested that CYP26A1 might regulate NK cells through chemokines. In conclusion, the present data suggest that silencing CYP26A1 expression/function can decrease the number of uNK cells and significantly increase the percentage of CD3 - CD49b + NK cells in the uteri of pregnant mice. These findings provide a new line of evidence correlating the deleterious effects of blocking CYP26A1 in pregnancy with the aberrant regulation of NK cells in the uterus., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Aim: To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM)., Methods: PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors., Conclusions: Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted., (© 2016 John Wiley & Sons Ltd.)

Interference with dynamic equilibrium of microtubule-tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure-activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine-site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D-QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs., (© 2015 John Wiley & Sons A/S.)

In the cation of the title hydrated salt, C19H21N2O2S2 (+)·I(-)·H2O, the benzo-thia-zolium ring system is approximately planar [maximum deviation = 0.0251 (15) Å], and it makes a small dihedral angle of 1.16 (18)° with the plane of the thio-phene ring. In the crystal, the cations, anions and crystalline water mol-ecules are linked by classical O-H⋯O, O-H⋯I and weak C-H⋯O hydrogn bonds, forming a three-dimensional supra-molecular network. π-π stacking is observed between parallel thia-zole rings of adjacent cations [centroid-centroid distance = 3.5945 (16) Å].

In the title compound, C8H11NO2S, the aldehyde group is approximately coplanar with the thio-phene ring [maximum deviation = 0.023 (2) Å]. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds into supra-molecular chains propagating along the a-axis direction.

In the title mol-ecule, C22H22N2O4, the eth-oxy-phenyl rings are oriented at dihedral angles of 69.31 (13) and 75.90 (13)° to the nitro-phenyl ring and are twisted to each other, making a dihedral angle of 78.55 (13)°. In the crystal, weak C-H⋯O hydrogen bonds and C-H⋯π inter-action link the mol-ecules into a three-dimensional supra-molecular architecture.

In the title compound, C24H18N2OS, the pyridine and the two phenyl rings are oriented at dihedral angles of 10.1 (5), 71.7 (6) and 68.7 (5)°, respectively, to the central thio-phene ring. In the crystal, pairs of weak C-H⋯O hydrogen bonds link inversion-related mol-ecules, forming dimers. The dimers are linked by further weak C-H⋯O hydrogen bonds, forming chains running along the a-axis direction.

In the cation of the title salt, C(18)H(23)N(2) (+)·C(24)H(20)B(-), the pyridine ring forms a dihedral angle of 14.23 (6)° with the benzene ring. One of the ethyl groups of the cation was refined as disordered over two sets of sites with equal occupancies.

In the title compound, C(15)H(12)ClN(3)O(2)S(2), the dihedral angle between the aromatic rings is 89.71 (10)°. In the crystal, inversion dimers linked by pairs of N-H⋯S hydrogen bonds occur.

In the title mol-ecule, C(21)H(16)O(8), the dihedral angle between the ring systems is 58.5 (1)°. In the crystal, C-H⋯O inter-actions help to establish the packing.

In the title mol-ecule, C(17)H(22)N(2)O(3), the mean plane of the terminal (C=O)OMe fragment and the indole plane form a dihedral angle of 78.94 (3)°. Inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into chains extended along the c axis. The crystal packing exhibits π-π inter-actions, indicated by the short distance of 3.472 (2) Å between the centroids of the five-membered heterocycles of neighbouring mol-ecules.

The title compound, C(10)H(12)N(2)O(2), was synthesized by cyclization of 3-(1-ethyl-pyrrole-2-carboxamido)propanoic acid in the presence of polyphospho-ric acid and diphospho-rus pentoxide. In the crystal structure, adjacent mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains extending along the b axis.

The title compound, C(10)H(14)N(2)O(3)·H(2)O, was synthesized by alkyl-ation of methyl 3-(1H-pyrrole-2-carboxamido)-propion-ate with ethyl bromide, followed by saponification and acidification. In the crystal structure, inter-molecular O-H⋯O and N-H⋯O hydrogen bonds link the mol-ecules, forming layers parallel to the ac plane.

In the title compound, C(5)H(5)NO(2), the pyrrole ring and its carboxyl substituent are close to coplanar, with a dihedral angle of 11.7 (3)° between the planes. In the crystal structure, adjacent mol-ecules are linked by pairs of O-H⋯O hydrogen bonds to form inversion dimers. Additional N-H⋯O hydrogen bonds link these dimers into chains extending along the a axis.

In the crystal structure of the title compound, C(8)H(10)N(2)O(3), mol-ecules are linked by N-H⋯O hydrogen bonds, forming ribbons of centrosymmetric dimers extending along the c axis.