Abstract Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. ...Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation.
Hepatic cancer is among the most recurrently detected malignancies worldwide and one of the main contributors to cancer-associated mortality. With few available therapeutic choices, there is an ...instant necessity to explore suitable options. In this aspect, Nanotechnology has been employed to explore prospective chemotherapeutic approaches, especially for cancer treatment. Nanotechnology is concerned with the biological and physical properties of nanoparticles in the therapeutic use of drugs. In the current work, formulation, and characterization of α-Fe2O3–Sodium Alginate-Eugenol nanocomposites (FSE NCs) using several approaches like SEM and TEM, UV–visible, FTIR, and PL spectroscopy, XRD, EDAX, and DLS studies have been performed. With an average size of 50 nm, the rhombohedral structure of NCs was identified. Further, their anticancer activity against Hep3B liver cancer cell lines has been performed by cell viability, dual staining, DCFH-DA, Annexin-V/-FITC/PI, cell cycle analysis methods, and PI3K/Akt/mTOR signaling proteins were studied to assess the anticancer effects of the NCs in Hep3B cells. Also, anti-cancer activity on animal modeling in-vivo using zebra fishes to hematological parameters, liver enzymes, and histopathology study effectiveness was noticed. Moreover, the NCs reduced the viability, elevated the ROS accumulation, diminished the membrane integrity, reduced the antioxidants, blocked the cell cycle, and triggered the PI3K/Akt/mTOR signaling axis that eventually resulted in cell death. As a result, FSE NCs possess huge potential for use as a possible anticancer candidate.
Hepatic stellate cells (HSC) are central players in liver fibrosis that when activated, proliferate, migrate to sites of liver injury, and secrete extracellular matrix. Obesity, a known risk factor ...for liver fibrosis is associated with reduced levels of adiponectin, a protein that inhibits liver fibrosis in vivo and limits HSC proliferation and migration in vitro. Adiponectin-mediated activation of adenosine monophosphate-activated kinase (AMPK) inhibits HSC proliferation, but the mechanism by which it limits HSC migration to sites of injury is unknown. Here we sought to elucidate how adiponectin regulates HSC motility. Primary rat HSCs were isolated and treated with adiponectin in migration assays. The in vivo actions of adiponectin were examined by treating mice with carbon tetrachloride for 12 weeks and then injecting them with adiponectin. Cell and tissue samples were collected and analyzed for gene expression, signaling, and histology. Serum from patients with liver fibrosis was examined for adiponectin and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Adiponectin administration into mice increased TIMP-1 gene and protein expression. In cultured HSCs, adiponectin promoted TIMP-1 expression and through binding of TIMP-1 to the CD63/β1-integrin complex reduced phosphorylation of focal adhesion kinase to limit HSC migration. In mice with liver fibrosis, adiponectin had similar effects and limited focal adhesion kinase phosphorylation. Finally, in patients with advanced fibrosis, there was a positive correlation between serum adiponectin and TIMP-1 levels. In sum, these data show that adiponectin stimulates TIMP-1 secretion by HSCs to retard their migration and contributes to the anti-fibrotic effects of adiponectin.
Adiponectin has been shown to limit liver fibrosis, but the molecular mechanisms remain unknown.
In vitro and in vivo adiponectin increases TIMP-1 secretion, which binds to the CD63/β1-integrin complex to decrease FAK activity and stellate cell migration.
Adiponectin-promoted TIMP-1 plays an important role in limiting liver fibrosis.
Targeting adiponectin signaling could be a useful way to limit liver fibrosis.
The role of AdipoR1 and AdipoR2 in liver fibrosis Alzahrani, Badr; Iseli, Tristan; Ramezani-Moghadam, Mehdi ...
Biochimica et biophysica acta. Molecular basis of disease,
03/2018, Volume:
1864, Issue:
3
Journal Article
Peer reviewed
Open access
Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought ...to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl4) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-α1 and α-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects.
•The absence of AdipoR1 or AdipoR2 is not essential for liver fibrosis in vivo.•AdipoR2 loss is associated with an enhanced fibrotic signature.•In activated HSCs, AdipoR2 is necessary for mediating APN's anti-fibrotic responses and cell migration.•APN is unable to activate AMPK in the absence of AdipoR2 in vitro.
Streptococcus gordonii is a gram-positive, mutualistic bacterium found in the human body. It is found in the oral cavity, upper respiratory tract, and intestines, and presents a serious clinical ...problem because it can lead to opportunistic infections in individuals with weakened immune systems. Streptococci are the most prevalent inhabitants of oral microbial communities, and are typical oral commensals found in the human oral cavity. These streptococci, along with many other oral microbes, produce multispecies biofilms that can attach to salivary pellicle components and other oral bacteria via adhesin proteins expressed on the cell surface. Antibiotics are effective against this bacterium, but resistance against antibodies is increasing. Therefore, a more effective treatment is needed. Vaccines offer a promising method for preventing this issue. This study generated a multi-epitope vaccine against Streptococcus gordonii by targeting the completely sequenced proteomes of five strains. The vaccine targets are identified using a pangenome and subtractive proteomic approach. In the present study, 13 complete strains out of 91 strains of S. gordonii are selected. The pangenomics results revealed that out of 2835 pan genes, 1225 are core genes. Out of these 1225 core genes, 643 identified as non-homologous proteins by subtractive proteomics. A total of 20 essential proteins are predicted from non-homologous proteins. Among these 20 essential proteins, only five are identified as surface proteins. The vaccine construct is designed based on selected B- and T-cell epitopes of the antigenic proteins with the help of linkers and adjuvants. The designed vaccine is docked against TLR2. The expression of the protein is determined using in silico gene cloning. Findings concluded that Vaccine I with adjuvant shows higher interactions with TLR2, suggesting that the vaccine has the ability to induce a humoral and cell-mediated response to treat and prevent infection; this makes it promising as a vaccine against infectious diseases caused by S. gordonii. Furthermore, validation of the vaccine construct is required by in vitro and in vivo trials to check its actual potency and safety for use to prevent infectious diseases caused by S. gordonii.
Colonization of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae as animal gut microbiota is a substantial global threat. This study aimed to determine the molecular ...characterization of bla.sub.SHV, bla.sub.TEM, and bla.sub.CTX-M variants in animals, as well as to evaluate the antimicrobial resistance conferred by these genes. We prospectively analyzed 1273 fecal specimens of farm and domestic animals for the isolation of enterobacteria that had the ESBL phenotype by using biochemical methods. The extracted genes were amplified by polymerase chain reaction and sequenced for the characterization of bla.sub.SHV, bla.sub.TEM, and bla.sub.CTX-M variants. The drug-resistance spectrum and hierarchical clusters were analyzed against 19 antibacterial agents. Out of 245 (19.2%) ESBL enterobacteria, 180 (75.5%) Escherichia coli and 34 (13.9%) Klebsiella pneumoniae were prevalent species. A total of 73.9% bla.sub.CTX-M, 26.1% bla.sub.TEM, and 14.2% bla.sub.SHV were found among the enterobacteria; however, their association with farm or domestic animals was not statistically significant. The distribution of bla gene variants showed the highest number of bla.sub.CTX-M-1 (133; 54.3%), followed by bla.sub.CTX-M-15 (28; 11.4%), bla.sub.TEM-52 (40; 16.3%), and bla.sub.SHV-12 (22; 9%). In addition, 84.5% of the enterobacteria had the integrons intI1. We observed #177;100% enterobacteria resistant to cephalosporin, 7 (2.9%) to colistin (minimum inhibitory concentration breakpoint greater than or equal to4 mug/mL), 9 (3.7%) to piperacillin-tazobactam, 11 (4.5%) to imipenem, 14 (5.7%) to meropenem, and 18 (7.3%) to cefoperazone-sulbactam, without statistically significant association. Animal gut microbiota contain a considerable number of bla.sub.CTX-M, bla.sub.TEM, bla.sub.SHV, and integrons, which are a potential source of acquired extensive drug resistance in human strains and leaves fewer therapeutic substitutes.
Dysfunctional or death of retinal photoreceptors is an irreversible phenomenon that is closely associated with a broad range of retinal degenerative diseases, such as retinitis pigmentosa and ...age-related macular degeneration (AMD), resulting in successive loss of visual function and blindness. In search for viable treatment for retinal degenerative diseases, mesenchymal stem cells (MSCs) has demonstrated promising therapeutic capabilities to repair and replace damaged photoreceptor cells in both in vitro and in vivo conditions. Nevertheless, the dearth of MSC differentiation capacity into photoreceptors has limited its use in cell replacement therapy. Erythropoietin (EPO) has vital role in early neural retinal cell differentiation and demonstrated rescue potential on dying photoreceptor cells. Hence, we aimed to evaluate the differentiation capacity of MSCs into photoreceptor cells in the presence of human EPO protein. We derived the MSC from human Wharton's jelly of umbilical cord and transduced the cells with lentivirus particles encoding EPO and green fluorescent protein (GFP) as reporter gene. The transduced cells were selectively cultured and induced to differentiate into photoreceptors by exposing to photoreceptor differentiation cocktail. Our preliminary results showed that transduced cells exposed to induction medium had an enhanced differentiation capacity when compared to non-transduced cells. Our results demonstrated a novel strategy to increase the yield of in vitro photoreceptor differentiation and may be potentially useful in improving the efficiency of stem cell transplantation for ocular disorders.
The differentiation of mesenchymal stem cells expressing erythropoietin (MSC-EPO) into rod photoreceptors. In the presence of taurine, these genetically-modified cells showed enhanced differentiation potential when compared to unmodified cells. Erythropoietin (EPO) could bind to its cognate receptor to activate a cascade of downstream signaling pathways such as Wingless/Integrated (Wnt), while inhibiting others including glycogen synthase kinase 3β (GSK-3β). These, in turn, lead to the up-regulation of genes involved in neurogenesis. This receptor is present in retinal neurons and hence, suggests a non-hematopoietic role in the eye. Other possible signaling pathways have also been discussed in our previous review (Ding et al., 15). Display omitted
•Enhanced rod photoreceptor cell differentiation with transduced, erythropoietin-expressing mesenchymal stem cells.•Photoreceptor differentiation of transduced mesenchymal stem cells with taurine showed upregulated RHO and CRX markers.•Presentation of typical neuronal phenotype morphology in transduced mesenchymal stem cells.
The present study investigated the cytotoxicity and proapoptotic properties of iron oxide-sodium-alginate-thymoquinone nanocomposites against breast cancer MDA-MB-231 cells in vitro and in silico. ...This study used chemical synthesis to formulate the nanocomposite. Electron microscopies such as scanning (SEM) and transmission (TEM), Fourier transform infrared (FT-IR), Ultraviolet-Visible, Photoluminescence spectroscopy, selected area (electron) diffraction (SAED), energy dispersive X-ray analysis (EDX), and X-ray diffraction studies (XRD) were used to characterize the synthesized ISAT-NCs and the average size of them was found to be 55 nm. To evaluate the cytotoxic, antiproliferative, and apoptotic potentials of ISAT-NCs on MDA-MB-231 cells, MTT assays, FACS-based cell cycle studies, annexin-V-PI staining, ELISA, and qRT-PCR were used. PI3K-Akt-mTOR receptors and thymoquinone were predicted using in-silico docking studies. Cell proliferation is reduced in MDA-MB-231 cells due to ISAT-NC cytotoxicity. As a result of FACS analysis, ISAT-NCs had nuclear damage, ROS production, and elevated annexin-V levels, which resulted in cell cycle arrest in the S phase. The ISAT-NCs in MDA-MB-231 cells were found to downregulate PI3K-Akt-mTOR regulatory pathways in the presence of inhibitors of PI3K-Akt-mTOR, showing that these regulatory pathways are involved in apoptotic cell death. We also predicted the molecular interaction between thymoquinone and PI3K-Akt-mTOR receptor proteins using in-silico docking studies which also support PI3K-Akt-mTOR signaling inhibition by ISAT-NCs in MDA-MB-231 cells. As a result of this study, we can conclude that ISAT-NCs inhibit the PI3K-Akt-mTOR pathway in breast cancer cell lines, causing apoptotic cell death.
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