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Human & Experimental Toxicology 2022Lung adenocarcinoma (LUAD) is a malignant tumor that occurs in the lungs. Numerous reports have substantiated the participation of long non-coding RNAs (lncRNAs) in the...
Lung adenocarcinoma (LUAD) is a malignant tumor that occurs in the lungs. Numerous reports have substantiated the participation of long non-coding RNAs (lncRNAs) in the tumorigenesis of LUAD. Previously, lncRNA alpha-2-macroglobulin antisense RNA 1 (A2M-AS1) was confirmed to be an important regulator in the biological processes of LUAD and dysregulation of A2M-AS1 was associated with non-small cell lung cancer (NSCLC) progression. However, the precise mechanism of A2M-AS1 in LUAD has not been elucidated. Therefore, our study was designed to investigate the detailed molecular mechanism of A2M-AS1 in LUAD. Herein, the expression of lncRNA A2M-AS1, microRNA (miRNA) miR-587, and bone morphogenetic protein 3 (BMP3) in LUAD cell lines and tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. The viability, proliferation, migration and invasion of LUAD cells were tested by cell counting kit-8 (CCK-8), colony formation and Transwell assays. In vivo tumor growth was investigated by xenograft animal experiment. Interactions among A2M-AS1, miR-587 and BMP3 were measured by RNA pulldown and luciferase reporter assays. In this study, A2M-AS1 was downregulated in LUAD tissues and cells and related to poor prognosis in LUAD patients. A2M-AS1 overexpression suppressed LUAD cell proliferation, migration and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, A2M-AS1 directly bound with miR-587 to promote BMP3 expression in LUAD cells. Low expression of BMP3 was found in LUAD tissues and cells and was closely correlated with poor prognosis in LUAD patients. BMP3 deficiency reserved the inhibitory influence of A2M-AS1 overexpression on LUAD cell behaviors. Overall, A2M-AS1 inhibits cell growth and aggressiveness via regulating the miR-587/BMP3 axis in LUAD.
Topics: Animals; Humans; Adenocarcinoma; alpha-Macroglobulins; Bone Morphogenetic Protein 3; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Lung; Lung Neoplasms; MicroRNAs; RNA, Long Noncoding; Adenocarcinoma of Lung; Neoplasm Invasiveness; Neoplasm Metastasis; Cell Survival; Disease Progression
PubMed: 36461613
DOI: 10.1177/09603271221138971 -
International Journal of Molecular... Nov 2022Articular cartilage (AC) defects are frequent but hard to manage. Osteoarthritis (OA) is a musculoskeletal illness that afflicts between 250 and 500 million people in... (Review)
Review
Articular cartilage (AC) defects are frequent but hard to manage. Osteoarthritis (OA) is a musculoskeletal illness that afflicts between 250 and 500 million people in the world. Even though traditional OA drugs can partly alleviate pain, these drugs cannot entirely cure OA. Since cartilaginous tissue of the joints has a poor self-repair capacity and very poor proliferative ability, the healing of injured cartilaginous tissue of the joint has not been accomplished so far. Consequently, the discovery of efficacious mediations and regenerative treatments for OA is needed. This manuscript reviews the basic concepts and the recent developments on the molecular mechanisms of cartilage repair and their potential clinical applications. For this purpose, a literature exploration was carried out in PubMed for the years 2020, 2021, and 2022. On 31 October 2022 and using "cartilage repair molecular mechanisms" as keywords, 41 articles were found in 2020, 42 in 2021, and 36 in 2022. Of the total of 119 articles, 80 were excluded as they were not directly related to the title of this manuscript. Of particular note are the advances concerning the mechanisms of action of hyaluronic acid, mesenchymal stem cells (MSCs), nanotechnology, enhancer of zeste 2 polycomb repressive complex 2 subunit (EHZ2), hesperetin, high mobility group box 2 (HMGB2), α2-macroglobulin (α2M), proteoglycan 4 (Prg4)/lubricin, and peptides related to cartilage repair and treatment of OA. Despite the progress made, current science has not yet achieved a definitive solution for healing AC lesions or repairing cartilage in the case of OA. Therefore, further research into the molecular mechanisms of AC damage is needed in the coming decades.
Topics: Humans; Cartilage, Articular; Osteoarthritis; Mesenchymal Stem Cells
PubMed: 36430749
DOI: 10.3390/ijms232214272 -
Journal of Dairy Science Jan 2023The composition and content of goat milk proteins are affected by many factors and have been extensively studied. However, variation in whey protein composition in goat...
The composition and content of goat milk proteins are affected by many factors and have been extensively studied. However, variation in whey protein composition in goat milk throughout the lactation cycle has not been clarified. In the current study, 15 dairy goats were selected, and milk samples were collected at 1, 3, 30, 90, 150, and 240 d after delivery. Whey proteins were separated and digested and then identified using data-independent acquisition (DIA) and data-dependent acquisition proteomics approaches. Protein profiles identified using DIA were consistent with those of the data-dependent acquisition proteomics approach according to clustering and principal component analyses. Significant differences in the abundance of 238 proteins around the lactation cycle were identified using the DIA approach. Developmental changes of the whey proteome corresponding to lactation stage were revealed: plasminogen, α-2-macroglobulin, and fibronectin levels decreased from d 1 to 240, whereas polymeric immunoglobulin receptor, nucleobindin 2, fatty acid-binding protein 3, and lactoperoxidase increased from d 1 to 240. Protein-protein interaction analysis showed that fibronectin with a higher degree of connectivity is a central node. The findings are of great significance to better understanding the potential role of specific proteins and the mechanism of protein biosynthesis or intercellular transport in the mammary glands related to the physiological changes of dairy goats.
Topics: Female; Animals; Whey Proteins; Proteomics; Fibronectins; Lactation; Milk Proteins; Goats
PubMed: 36424323
DOI: 10.3168/jds.2022-21800 -
ASN Neuro 2022Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They... (Review)
Review
Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They strongly monitor retinal environment and, in response to retinal imbalance, activate neuroprotective mechanisms mainly characterized by the increase of glial fibrillary acidic protein (GFAP). Under these circumstances, if homeostasis is not reestablished, the retina can be severely injured and GFAP contributes to neuronal degeneration, as they occur in several proliferative retinopathies such as diabetic retinopathy, sickle cell retinopathy and retinopathy of prematurity. In addition, MGCs have an active participation in inflammatory responses releasing proinflammatory mediators and metalloproteinases to the extracellular space and vitreous cavity. MGCs are also involved in the retinal neovascularization and matrix extracellular remodeling during the proliferative stage of retinopathies. Interestingly, low-density lipoprotein receptor-related protein 1 (LRP1) and its ligand α-macroglobulin (αM) are highly expressed in MGCs and they have been established to participate in multiple cellular and molecular activities with relevance in retinopathies. However, the exact mechanism of regulation of retinal LRP1 in MGCs is still unclear. Thus, the active participation of MGCs and LRP1 in these diseases, strongly supports the potential interest of them for the design of novel therapeutic approaches. In this review, we discuss the role of LRP1 in the multiple MGCs activities involved in the development and progression of proliferative retinopathies, identifying opportunities in the field that beg further research in this topic area.MGCs and LRP1 are active players in injured retinas, participating in key features such as gliosis and neurotoxicity, neovascularization, inflammation, and glucose control homeostasis during the progression of ischemic diseases, such as proliferative retinopathies.
Topics: Humans; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Low Density Lipoprotein Receptor-Related Protein-1; Retina; Retinal Neovascularization
PubMed: 36317314
DOI: 10.1177/17590914221136365 -
3 Biotech Nov 2022Proteins of the macroglobulin family are prime targets of venom enzymes in snake bite. A massive reduction in the active concentration of these multifunctional proteins...
Proteins of the macroglobulin family are prime targets of venom enzymes in snake bite. A massive reduction in the active concentration of these multifunctional proteins in snake bite, makes the living system vulnerable to dysregulation. This study investigates the ability of Indian polyvalent anti-snake venom (ASV), methanolic extract of (MAP) and their combination in rescuing human alpha 2-macroglobulin (A2MG) and its homologues in rat plasma, from inactivation by (N.N) venom enzymes. In-vitro experiments were conducted with heparinized human plasma and in-vivo experiments with female Wistar rats. Along with appropriate controls, there were 3 test groups in in-vitro and 8 test groups in in-vivo experiments. The in-vitro test groups were exposed to N.N venom for zero, 30 or 90 min prior to incubation with ASV or MAP or reduced ASV supplemented with MAP and incubated for 16 h at 37 °C. Chymotrypsin-bound esterase (CTBE) activity of A2MG was estimated. Rats were administered the venom intramuscularly and treated with ASV/MAP/ASV + MAP. CTBE activity of macroglobulin homologues was measured on day 1, 7 and 14. Survival of animals was noted. In human plasma, addition of ASV or MAP or ASV + MAP prevented loss of A2MG activity maximally to the extent of 88-100% ( = 0.001). In rats, reduced concentration of ASV supplemented with MAP showed complete rescue of macroglobulin homologues and 90% survival. The compulsive evidence from this study, underscores the merits of using this multipronged strategy in rescuing the macroglobulins and improving survival in envenomation due to N.N.
PubMed: 36276455
DOI: 10.1007/s13205-022-03379-w -
Frontiers in Oncology 2022Multiple myeloma (MM) is a hematological malignancy, and intramedullary spinal cord metastasis is extremely rare.
BACKGROUND
Multiple myeloma (MM) is a hematological malignancy, and intramedullary spinal cord metastasis is extremely rare.
METHODS
Clinical and radiological data were collected from electronic medical records as well as a literature review of reported cases.
RESULTS
We report a rare case of IgA-LAM stage IIB MM with involvement of the spinal cord and peripheral nervous system. Laboratory studies showed elevated levels of serum β2-macroglobulin and cerebrospinal fluid protein. Electromyography revealed a demyelinating process with motor conduction blocks. On MRI, the lesions of MM bone marrow are characterized as a type of diffuse infiltration. MR neurography demonstrated an enhanced nodule in the thoracic segment with swelling of the cervicothoracic segments of the spinal cord. Moreover, swelling and hypertrophy of the entire nerve branchial, lumbosacral plexus, and cauda equina were detected, accompanied by myofascitis and denervated muscles. Ultimately, the condition of the patient deteriorated quickly and she died with a diagnosis of refractory MM.
CONCLUSION
MRI not only has the advantage of displaying the primary involved site of the bone marrow but also facilitates detecting extramedullary hematopoietic MM, such as infiltrating sites of the central and/or peripheral nervous system.
PubMed: 36276061
DOI: 10.3389/fonc.2022.991246 -
Scientific Reports Oct 2022LDL Receptor-related Protein-1 (LRP1/CD91) binds diverse ligands, many of which activate cell-signaling. Herein, we compared three LRP1 ligands that inhibit inflammatory...
The LRP1/CD91 ligands, tissue-type plasminogen activator, α-macroglobulin, and soluble cellular prion protein have distinct co-receptor requirements for activation of cell-signaling.
LDL Receptor-related Protein-1 (LRP1/CD91) binds diverse ligands, many of which activate cell-signaling. Herein, we compared three LRP1 ligands that inhibit inflammatory responses triggered by lipopolysaccharide (LPS), including: enzymatically-inactive tissue-type plasminogen activator (EI-tPA); activated α-macroglobulin (αM); and S-PrP, a soluble derivative of nonpathogenic cellular prion protein (PrP). In bone marrow-derived macrophages, the N-methyl-D-aspartate receptor was essential for all three LRP1 ligands to activate cell-signaling and inhibit LPS-induced cytokine expression. Intact lipid rafts also were essential. Only αM absolutely required LRP1. LRP1 decreased the EI-tPA concentration required to activate cell-signaling and antagonize LPS but was not essential, mimicking its role as a S-PrP co-receptor. Membrane-anchored PrP also functioned as a co-receptor for EI-tPA and αM, decreasing the ligand concentration required for cell-signaling and LPS antagonism; however, when the concentration of EI-tPA or αM was sufficiently increased, cell-signaling and LPS antagonism occurred independently of PrP. S-PrP is the only LRP1 ligand in this group that activated cell-signaling independently of membrane-anchored PrP. EI-tPA, αM, and S-PrP inhibited LPS-induced LRP1 shedding from macrophages, a process that converts LRP1 into a pro-inflammatory product. Differences in the co-receptors required for anti-inflammatory activity may explain why LRP1 ligands vary in ability to target macrophages in different differentiation states.
Topics: Pregnancy; Female; Humans; Lipopolysaccharides; Ligands; Prion Proteins; Tissue Plasminogen Activator; Pregnancy-Associated alpha 2-Macroglobulins; Receptors, N-Methyl-D-Aspartate; Low Density Lipoprotein Receptor-Related Protein-1; Cytokines
PubMed: 36266319
DOI: 10.1038/s41598-022-22498-1 -
Frontiers in Immunology 2022Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the...
Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the coagulation system in the pathogenesis of COVID-19. However, the multifactorial nature of thrombosis complicates the prediction of thrombotic events based on a single hemostatic variable. We developed and validated a neural net for the prediction of COVID-19-related thrombosis. The neural net was developed based on the hemostatic and general (laboratory) variables of 149 confirmed COVID-19 patients from two cohorts: at the time of hospital admission (cohort 1 including 133 patients) and at ICU admission (cohort 2 including 16 patients). Twenty-six patients suffered from thrombosis during their hospital stay: 19 patients in cohort 1 and 7 patients in cohort 2. The neural net predicts COVID-19 related thrombosis based on C-reactive protein (relative importance 14%), sex (10%), thrombin generation (TG) time-to-tail (10%), α-Macroglobulin (9%), TG curve width (9%), thrombin-α-Macroglobulin complexes (9%), plasmin generation lag time (8%), serum IgM (8%), TG lag time (7%), TG time-to-peak (7%), thrombin-antithrombin complexes (5%), and age (5%). This neural net can predict COVID-19-thrombosis at the time of hospital admission with a positive predictive value of 98%-100%.
Topics: Antithrombins; C-Reactive Protein; COVID-19; Fibrinolysin; Hemostatics; Humans; Immunoglobulin M; Neural Networks, Computer; Predictive Value of Tests; Thrombin; Thrombosis
PubMed: 36248875
DOI: 10.3389/fimmu.2022.977443 -
Frontiers in Cell and Developmental... 2022Septate junctions (SJs) serve as occluding barriers in invertebrate epithelia. In , at least 30 genes are required for the formation or maintenance of SJs....
Septate junctions (SJs) serve as occluding barriers in invertebrate epithelia. In , at least 30 genes are required for the formation or maintenance of SJs. Interestingly, loss-of-function mutations in core SJ components are embryonic lethal, with defects in developmental events such as head involution and dorsal closure (DC) that occur prior to the formation of a mature SJ, indicating a role for these proteins in mid-embryogenesis independent of their occluding function. To understand this novel function in development, we examined loss-of-function mutations in three core SJ proteins during the process of DC. DC occurs during mid-embryogenesis to seal a dorsal gap in the epidermis following germ band retraction. Closure is driven by contraction of the extraembryonic amnioserosa cells that temporarily cover the dorsal surface and by cell shape changes (elongation) of lateral epidermal cells that bring the contralateral sheets together at the dorsal midline. Using live imaging and examination of fixed tissues, we show that early events in DC occur normally in SJ mutant embryos, but during later closure, , and mutant embryos exhibit slower rates of closure and display aberrant cells shapes in the dorsolateral epidermis, including dorsoventral length and apical surface area. SJ mutant embryos also show mild defects in actomyosin structures along the leading edge, but laser cutting experiments suggest similar tension and viscoelastic properties in SJ mutant versus wild type epidermis. In a high percentage of SJ mutant embryos, the epidermis tears free from the amnioserosa near the end of DC and live imaging and immunostaining reveal reduced levels of E-cadherin, suggesting that defective adhesion may be responsible for these tears. Supporting this notion, reducing E-cadherin by half significantly enhances the penetrance of DC defects in mutant embryos.
PubMed: 36238688
DOI: 10.3389/fcell.2022.947444 -
Cells Sep 2022Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial...
Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch's membrane and visual function.
Topics: Antibodies, Blocking; Culture Media, Conditioned; Endothelial Cells; Female; Gelatinases; Humans; Matrix Metalloproteinase 2; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Protease Inhibitors; Recombinant Proteins; Retinal Pigment Epithelium; Transcription Factors; Vascular Endothelial Growth Factor A
PubMed: 36230937
DOI: 10.3390/cells11192975