scholarly journals Secretory mouse quiescin sulfhydryl oxidase 1 aggregates defected human and mouse spermatozoa in vitro and in vivo

iScience ◽  
2021 ◽  
Vol 24 (10) ◽  
pp. 103167
Author(s):  
Tse-En Wang ◽  
Ling-Yu Yeh ◽  
Robert Kuo-Kuang Lee ◽  
Chung-Hao Lu ◽  
Tsung-Hsien Yang ◽  
...  
Keyword(s):  
Sulfhydryl Oxidase ◽  
Quiescin Sulfhydryl Oxidase ◽  
Human And Mouse

scholarly journals miR-146a-5p Promotes Chondrocyte Apoptosis and Inhibits Autophagy of Osteoarthritis by Targeting NUMB

Cartilage ◽  
2021 ◽  
pp. 194760352110235
Author(s):  
Hongjun Zhang ◽  
Wendi Zheng ◽  
Du Li ◽  
Jia Zheng
Keyword(s):  
Caspase 3 ◽  
Cartilage Tissue ◽  
Luciferase Reporter ◽  
Chondrocyte Apoptosis ◽  
Knee Cartilage ◽  
Before And After ◽  
Related Proteins ◽  
Human And Mouse

Objective miR-146a-5p was found to be significantly upregulated in cartilage tissue of patients with osteoarthritis (OA). NUMB was shown to be involved in the autophagy regulation process of cells. We aimed to learn whether NUMB was involved in the apoptosis or autophagy process of chondrocytes in OA and related with miR-146a-5p. Methods QRT-PCR was used to detect miR-146a-5p level in 22 OA cartilage tissues and 22 controls. The targets of miR-146a-5p were analyzed using software and the luciferase reporter experiment. The apoptosis and autophagy, and related proteins were detected in chondrocytes treated with miR-146a-5p mimic/inhibitor or pcDNA3.1-NUMB/si-NUMB and IL-1β, respectively. In vivo experiment, intra-articular injection of miR-146a-5p antagomir/NC was administered at the knee of OA male mice before and after model construction. Chondrocyte apoptosis and the expression of apoptosis and autophagy-related proteins were also detected. Results miR-146a-5p was highly expressed in knee cartilage tissue of patients with OA, while NUMB was lowly expressed and negatively regulated by miR-146a-5p. Upregulation of miR-146a-5p can promote cell apoptosis and reduce autophagy of human and mouse chondrocytes by modulating the levels of cleaved caspase-3, cleaved PARP, Bax, Beclin 1, ATG5, p62, LC3-I, and LC3-II. Increasing the low level of NUMB reversed the effects of miR-146a-5p on chondrocyte apoptosis and autophagy. Intra-articular injection of miR-146a-5p antagomir can also reverse the effects of miR-146a-5p on the apoptosis and autophagy of knee joint chondrocytes in OA mice. Conclusion Downregulation of miR-146a-5p suppresses the apoptosis and promotes autophagy of chondrocytes by targeting NUMB in vivo and in vitro.

scholarly journals Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Domenico Mattoscio ◽  
Elisa Isopi ◽  
Alessia Lamolinara ◽  
Sara Patruno ◽  
Alessandro Medda ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Growth Curve ◽  
Immune Cells ◽  
Cancer Growth ◽  
Resolvin D1 ◽  
Anti Cancer ◽  
Classical Monocytes ◽  
Human And Mouse

Abstract Background Innovative therapies to target tumor-associated neutrophils (PMN) are of clinical interest, since these cells are centrally involved in cancer inflammation and tumor progression. Resolvin D1 (RvD1) is a lipid autacoid that promotes resolution of inflammation by regulating the activity of distinct immune and non-immune cells. Here, using human papilloma virus (HPV) tumorigenesis as a model, we investigated whether RvD1 modulates PMN to reduce tumor progression. Methods Growth-curve assays with multiple cell lines and in vivo grafting of two distinct HPV-positive cells in syngeneic mice were used to determine if RvD1 reduced cancer growth. To investigate if and how RvD1 modulates PMN activities, RNA sequencing and multiplex cytokine ELISA of human PMN in co-culture with HPV-positive cells, coupled with pharmacological depletion of PMN in vivo, were performed. The mouse intratumoral immune cell composition was evaluated through FACS analysis. Growth-curve assays and in vivo pharmacological depletion were used to evaluate anti-tumor activities of human and mouse monocytes, respectively. Bioinformatic analysis of The Cancer Genome Atlas (TCGA) database was exploited to validate experimental findings in patients. Results RvD1 decreased in vitro and in vivo proliferation of human and mouse HPV-positive cancer cells through stimulation of PMN anti-tumor activities. In addition, RvD1 stimulated a PMN-dependent recruitment of classical monocytes as key determinant to reduce tumor growth in vivo. In human in vitro systems, exposure of PMN to RvD1 increased the production of the monocyte chemoattractant protein-1 (MCP-1), and enhanced transmigration of classical monocytes, with potent anti-tumor actions, toward HPV-positive cancer cells. Consistently, mining of immune cells infiltration levels in cervical cancer patients from the TCGA database evidenced an enhanced immune reaction and better clinical outcomes in patients with higher intratumoral monocytes as compared to patients with higher PMN infiltration. Conclusions RvD1 reduces cancer growth by activating PMN anti-cancer activities and encouraging a protective PMN-dependent recruitment of anti-tumor monocytes. These findings demonstrate efficacy of RvD1 as an innovative therapeutic able to stimulate PMN reprogramming to an anti-cancer phenotype that restrains tumor growth.

scholarly journals Synaptopodin: An Actin-associated Protein in Telencephalic Dendrites and Renal Podocytes

1997 ◽  
Vol 139 (1) ◽  
pp. 193-204 ◽  
Author(s):  
Peter Mundel ◽  
Hans W. Heid ◽  
Thomas M. Mundel ◽  
Meike Krüger ◽  
Jochen Reiser ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Cultured Cells ◽  
Rat Kidney ◽  
Amino Acid Sequences ◽  
Cdna Clones ◽  
Globular Domain ◽  
Postnatal Maturation ◽  
Human And Mouse

Synaptopodin is an actin-associated protein of differentiated podocytes that also occurs as part of the actin cytoskeleton of postsynaptic densities (PSD) and associated dendritic spines in a subpopulation of exclusively telencephalic synapses. Amino acid sequences determined in purified rat kidney and forebrain synaptopodin and derived from human and mouse brain cDNA clones show no significant homology to any known protein. In particular, synaptopodin does not contain functional domains found in receptor-clustering PSD proteins. The open reading frame of synaptopodin encodes a polypeptide with a calculated Mr of 73.7 kD (human)/74.0 kD (mouse) and an isoelectric point of 9.38 (human)/9.27 (mouse). Synaptopodin contains a high amount of proline (∼20%) equally distributed along the protein, thus virtually excluding the formation of any globular domain. Sequence comparison between human and mouse synaptopodin revealed 84% identity at the protein level. In both brain and kidney, in vivo and in vitro, synaptopodin gene expression is differentiation dependent. During postnatal maturation of rat brain, synaptopodin is first detected by Western blot analysis at day 15 and reaches maximum expression in the adult animal. The exclusive synaptopodin synthesis in the telencephalon has been confirmed by in situ hybridization, where synaptopodin mRNA is only found in perikarya of the olfactory bulb, cerebral cortex, striatum, and hippocampus, i.e., the expression is restricted to areas of high synaptic plasticity. From these results and experiments with cultured cells we conclude that synaptopodin represents a novel kind of proline-rich, actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and podocyte foot processes.

A Drosophila doublesex-related gene, terra, is involved in somitogenesis in vertebrates

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1259-1268 ◽  
Author(s):  
A. Meng ◽  
B. Moore ◽  
H. Tang ◽  
B. Yuan ◽  
S. Lin
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Dna Binding Domain ◽  
Related Gene ◽  
Presomitic Mesoderm ◽  
Zinc Finger Gene ◽  
Human And Mouse

The Drosophila doublesex (dsx) gene encodes a transcription factor that mediates sex determination. We describe the characterization of a novel zebrafish zinc-finger gene, terra, which contains a DNA binding domain similar to that of the Drosophila dsx gene. However, unlike dsx, terra is transiently expressed in the presomitic mesoderm and newly formed somites. Expression of terra in presomitic mesoderm is restricted to cells that lack expression of MyoD. In vivo, terra expression is reduced by hedgehog but enhanced by BMP signals. Overexpression of terra induces rapid apoptosis both in vitro and in vivo, suggesting that a tight regulation of terra expression is required during embryogenesis. Terra has both human and mouse homologs and is specifically expressed in mouse somites. Taken together, our findings suggest that terra is a highly conserved protein that plays specific roles in early somitogenesis of vertebrates.

scholarly journals Effect of mono-(2-ethylhexyl) phthalate on human and mouse fetal testis: In vitro and in vivo approaches

2012 ◽  
Vol 261 (1) ◽  
pp. 97-104 ◽  
Author(s):  
V. Muczynski ◽  
J.P. Cravedi ◽  
A. Lehraiki ◽  
C. Levacher ◽  
D. Moison ◽  
...  
Keyword(s):  
Fetal Testis ◽  
Ethylhexyl Phthalate ◽  
Human And Mouse

scholarly journals Nanoemulsions as Delivery Systems for Poly-Chemotherapy Aiming at Melanoma Treatment

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1198
Author(s):  
Chiara Dianzani ◽  
Chiara Monge ◽  
Gianluca Miglio ◽  
Loredana Serpe ◽  
Katia Martina ◽  
...  
Keyword(s):  
Mouse Cell ◽  
Advanced Melanoma ◽  
In Vivo Studies ◽  
Cell Models ◽  
Tumour Angiogenesis ◽  
Investigation Methods ◽  
Melanoma Treatment ◽  
Human And Mouse

Aims: Advanced melanoma is characterized by poor outcome. Despite the number of treatments having been increased over the last decade, current pharmacological strategies are only partially effective. Therefore, the improvement of the current systemic therapy is worthy of investigation. Methods: a nanotechnology-based poly-chemotherapy was tested at preclinical level. Temozolomide, rapamycin, and bevacizumab were co-loaded as injectable nanoemulsions for total parenteral nutrition (Intralipid®), due to suitable devices, and preliminarily tested in vitro on human and mouse cell models and in vivo on the B16-F10 melanoma mouse model. Results: Drug combination was efficiently loaded in the liquid lipid matrix of Intralipid®, including bevacizumab monoclonal antibody, leading to a fast internalization in tumour cells. An increased cytotoxicity towards melanoma cells, as well as an improved inhibition of tumour relapse, migration, and angiogenesis were demonstrated in cell models for the Intralipid®-loaded drug combinations. In preliminary in vivo studies, the proposed approach was able to reduce tumour growth significantly, compared to controls. A relevant efficacy towards tumour angiogenesis and mitotic index was determined and immune response was involved. Conclusions: In these preliminary studies, Intralipid® proved to be a safe and versatile poly-chemotherapy delivery system for advanced melanoma treatment, by acting on multiple mechanisms.

scholarly journals The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Madeline Niederkorn ◽  
Chiharu Ishikawa ◽  
Kathleen M. Hueneman ◽  
James Bartram ◽  
Emily Stepanchick ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Leukemic Cell ◽  
Human And Mouse ◽  
Acute Myeloid

AbstractUbiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.

scholarly journals PLA2G6 guards placental trophoblasts against ferroptotic injury

2020 ◽  
Vol 117 (44) ◽  
pp. 27319-27328
Author(s):  
Ofer Beharier ◽  
Vladimir A. Tyurin ◽  
Julie P. Goff ◽  
Jennifer Guerrero-Santoro ◽  
Kazuhiro Kajiwara ◽  
...  
Keyword(s):  
Lipid Hydroperoxides ◽  
Spontaneous Preterm Birth ◽  
Placental Dysfunction ◽  
Reoxygenation Injury ◽  
Oxidized Fatty Acid ◽  
Human And Mouse ◽  
Excessive Accumulation

The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specific manner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.

scholarly journals Phenotypic switch of human and mouse macrophages and resultant effects on apoptosis resistance in hepatocytes

2019 ◽  
Vol 25 (3) ◽  
pp. 176-185 ◽  
Author(s):  
Li Bai ◽  
Yu Chen ◽  
Sujun Zheng ◽  
Feng Ren ◽  
Ming Kong ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Apoptosis Resistance ◽  
Phenotypic Switch ◽  
Novel Treatments ◽  
Mouse Macrophages ◽  
Ifn Γ ◽  
Acute Insult ◽  
Human And Mouse

Acute-on-chronic liver failure (ACLF) carries a significant burden on critical care services and health care resources. However, the exact pathogenesis of ACLF remains to be elucidated, and novel treatments are desperately required. In our previous work, we utilized mice subjected to acute insult in the context of hepatic fibrosis to simulate the development of ACLF and documented the favorable hepatoprotection conferred by M2-like macrophages in vivo and in vitro. In the present study, we focused on the phenotypic switch of human and mouse macrophages and assessed the effects of this switch on apoptosis resistance in hepatocytes. For this purpose, human and mouse macrophages were isolated and polarized into M0, M(IFN-γ), M(IFN-γ→IL-4), M(IL-4) or M(IL-4→IFN-γ) subsets. Conditioned media (CM) from these subsets were applied to human and mouse hepatocytes followed by apoptosis induction. Cell apoptosis was evaluated by immunostaining for cleaved caspase-3. As a result, M(IFN-γ) or M(IL-4) macrophages switched their phenotype into M(IFN-γ→IL-4) or M(IL-4→IFN-γ) through reprogramming with IL-4 or IFN-γ, respectively. Importantly, hepatocytes pre-treated with M(IFN-γ→IL-4) CMs exhibited much weaker expression of cleaved caspase-3, compared to those pre-treated with M(IFN-γ) CM, and vice versa. Together, phenotypic switch of macrophages toward M(IL-4) phenotype confers hepatocytes enhanced resistance to apoptosis.

LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

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