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Bone Regeneration Effect of Cassia occidentalis Linn. Extract and Its Isolated Compounds
Published in Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay, Phytochemistry of Plants of Genus Cassia, 2021
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay
In C3H10T1/2 cells, luteolin promotes osteogenic differentiation and in 3T3-L1 cells, it inhibits adipogenic differentiation. These effects are mediated by heat shock protein, Dnajb1 (DnaJ Hsp40) (Kwon et al., 2016). In human osteogenic sarcoma cell line, Saos2, luteolin, and its 8-C-glucopyranose analog orientin increased mineral content upon the induction of differentiation in the presence of β-glycerophosphate. At >10 μM, luteolin decreased the mineral content likely due to a pro-oxidant impact. At 50 μM, luteolin had a cytotoxic effect on osteoblasts as assessed by LDH release. Both luteolin and orientin inhibited the production of pro-inflammatory cytokines (TNFα and IL-6) from osteoblasts as well as sclerostin. Suppression of sclerostin by luteolin is likely to promote the osteogenic Wnt signaling (Nash et al., 2015). Furthermore, luteolin protected MC3T3-E1 cells against oxidative damage caused by H2O2 and menadione (Fatokun et al., 2015). From these reports, it appears that luteolin promotes osteoblast function and inhibits osteoclast function.
Hepatic tumors
Published in Prem Puri, Newborn Surgery, 2017
Benjamin A. Farber, William J. Hammond, Michael P. La Quaglia
Fibrolamellar HCC (FLHCC) is a rare primary liver tumor that typically presents in children and young adult patients with no background history of liver disease or hepatitis, and sporadic cases have been reported in infants.162 The tumor was first described in 195645 as a variant of conventional HCC, but is now recognized as a unique pathologic entity. Patients typically do not have viral hepatitis or cirrhosis, and do not exhibit elevations in serum AFP. Recent advances in the tumor biology of FLHCC show a 400-kb deletion in one copy of chromosome 19 in tumor samples producing a chimeric transcript between the first exon of the heat shock protein, DNAJB1, with all but the first exon of the catalytic subunit of protein kinase A, PRKACA.163 This chimera is a functional kinase, and few other changes are seen in the genomic DNA.164 Total surgical resection is paramount in treatment of FLHCC, and outcomes have been reported to be more favorable for FLHCC than conventional HCC. Lymph node metastases are common, and presence of extrahepatic disease is a consistent, independent predictor of overall and recurrence-free survival.165 Recent transcriptomic evaluation of FLHCC shows key oncologically relevant pathways to have elevated transcription levels, including EGF/ErbB and Wnt signaling pathways, which may lead to new avenues of treatment. Ongoing clinical trials are evaluating the use of an oral aurora kinase A inhibitor, the transcript of which was found to be elevated in FLHCC tumor samples (ClinicalTrials.gov identifier: NCT02234986).166
Pediatric fibrolamellar hepatocellular carcinoma: case report and review of the literature
Published in Acta Chirurgica Belgica, 2021
Laura Depauw, Glenn De Weerdt, Ben Gys, Sofie Demeulenaere, Wouter Mebis, Dirk Ysebaert
Thanks to whole genome sequencing, major breakthroughs in the understanding of the pathogenesis of FL-HCC were made recently. FL-HCC has a deletion mutation which results in the fusion gene DNAJB1-PRKACA [12]. This leads to an enhanced cAMP-dependent PKA activity, which could promote additional transcriptional activation. The DNAJB1-PRKACA fusion gene is unique for and near-universal present in FL-HCC, which strongly suggests that the fusion protein is a primary driver of FL-HCC [17]. In this case report, the DNAJB1-PRKACA fusion gene has not been investigated, as whole genome sequencing is not a standard procedure and moreover expensive and time-consuming. The diagnosis of FL-HCC has been confirmed on both imaging and anatomopathological evaluation.
Transcriptomic analysis reveals the regulatory mechanism underlying the indirubin-mediated amelioration of dextran sulfate sodium-induced colitis in mice
Published in Pharmaceutical Biology, 2023
Zhe Liu, Jin-ru Zhang, Yong-xiang Huang, Xue-ying Li, Hai-peng Zhu, Rui-yi Yang, Song Chen
Compared with the control group, a total of 920 DEGs were identified. Among these, 627 and 295 were upregulated and downregulated, respectively, based on [linear] fold change ≥2 and adjusted P (Padj) cutoff <0.05. The top 10 upregulated and downregulated genes based on the ranking of P-values were then labelled (Figure 3(A)). Among these, Clec2j, Clca4b, Prss27, Nos2, and Prss22, as well as some pseudogenes and predicted genes, were the most markedly upregulated genes. Cxcl5 was the most prominently upregulated gene based on the fold change (Figure 3(A)). The most downregulated genes included those belonging to the heat shock protein (HSP) family (Hspa1a, Hspa1b, and Hsph1), DnaJ family (Dnaja1 and Dnajb1, which act as co-chaperones for heat shock protein 70), and Nr1d1, which encodes a ligand-sensitive transcription factor that negatively regulates core clock protein expression. A heatmap revealed that the clustered DEGs in the DSS model group were separate from those in the control group (Figure 3(B)). PPI analysis with the proteins corresponding to DEGs showed some hub genes, including HSP (including DnaJ), Nlrp3-Il1b, chemokines, hemoglobin (including Hbb-bt, Hbb-bs, Hba-a2, and Hba-a1), and haptoglobin (Hp) (Figure 3(C)). Functional KEGG pathways were also predicted. Among the top five enriched KEGG pathways, the IL-17 signalling pathway, cytokine–cytokine receptor interaction, African trypanosomiasis, and malaria were upregulated, whereas fat digestion and absorption pathways were downregulated (Figure 3(D)). The corresponding DEG-based transcriptions are shown in Figure 3(E). The dominant transcription factors include zinc finger (zf)-C2H2, Forkhead homeobox, and basic helix-loop-helix.
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
The components and mechanisms of secretory protein folding and quality control in the ER and cytosol have been extensively studied [58]. Association of F508del-CFTR with calnexin, an ER chaperone specific for N-glycosylated secretory proteins constituting the ‘Calnexin Cycle’, is prolonged compared to wild-type CFTR [59]. There are several well studied inhibitors of the glucosidases and mannosidases of the Calnexin Cycle [8,24]. The imino sugar derivative N-butyl-deoxynojirimycin or miglustat (Zavesca™) has been shown to have some CFTR corrector activity in cells [60] but this was not sustained in Phase 2a clinical trials. The ‘chaperome’ (proteins that interact with CFTR during its folding and quality control) includes many logical targets for proteostasis modulators. NBD1 is exposed to the cytosol therefore its most extensive interactions are with chaperones and quality control machinery in the cytosolic compartment. HSP90 was found to be important for CFTR trafficking through the use of its inhibitor geldanamycin [61]. HSC70 and its co-chaperone DNAJA1 interact with misfolded NBD1 and promote CFTR trafficking [62,63]. DNAJB1 also interacts with NBD1 but is less effective than DNAJA1. Proteomics studies have revealed that more HSP90, HSC70, HSP70 and DNAJB1 associate with F508del-CFTR than with wild-type CFTR, consistent with their roles in folding [64–66]. HSP70 also has a major role in the ERAD of CFTR through its association with the cytosolic E3 ubiquitin ligase CHIP, which acts independently of the ER-anchored E3 ligases RMA1 and gp78 [67–69]. Several HSC70/HSP70 co-chaperones regulate CFTR degradation by CHIP. HSP110 and CSPα promote its degradation [70,71] whereas BAG2 and HSPBP1 interfere with CHIP and their overexpression can increase CFTR trafficking [72–74]. DNAJB12 and DNAJB14 promote CFTR ERAD independently of CHIP, and most likely through the other E3 ligases [62,75,76]. These chaperones and co-chaperone components may impact the folding of other cellular proteins however they remain potential therapeutic targets for CFTR correctors.