IUBMB Life最新文献

Iron is an essential element for physiological cellular processes, but is toxic in excess. Iron overload diseases are commonly associated with low bone mass. Increased bone resorption by osteoclasts as well as decreased bone formation by osteoblasts have been implicated in bone loss under iron overload conditions. However, the exact contribution of individual cell types has not yet been formally tested. In this study, we aimed to investigate the role of osteoclast precursors in iron overload-induced bone loss. To that end, we used clodronate liposomes to deplete phagocytic cells (including macrophages and osteoclast precursors) in male C57BL/6J mice that were exposed to ferric derisomaltose. Bone microarchitecture and bone turnover were assessed after 4 weeks. The application of clodronate resulted in the efficient depletion of circulating myeloid-lineage cells by about 70%. Depletion of osteoclast precursors mitigated iron overload-induced trabecular bone loss at the lumbar vertebrae and distal femur. While clodronate treatment led to a profound inhibition of bone turnover in control mice, it significantly reduced osteoclast numbers in iron-treated mice without further impacting the bone formation rate or serum PINP levels. Our observations suggest that even though bone formation is markedly suppressed by iron overload, osteoclasts also play a key role in iron overload-induced bone loss and highlight them as potential therapeutic targets.

In our present study, we investigated the interaction between HSCs and HCC, also explored the molecular mechanism. Clinical samples were collected from HCC and adjacent tissue with different degree of liver fibrosis. HCC cells were co-cultured with LX-2 cell by Transwell system or cultured with conditioned medium (CM), which was collected from LX-2. The tumor spheroid growth and colony formation analyses were performed to evaluate the cell stemness. Flow cytometry analysis was conducted on cell apoptosis after 5-Fu treatment. Co-immunoprecipitation assay confirmed the interaction between BMI1 and PAK4. Our results showed that BMI1 was highly expressed in HCC and was correlated with HCC liver fibrosis. Both co-cultured with LX-2 and cultured with CM promoted HCC stemness, also increased KGF level and BMI1 expression. KGF treatment had a similar effect with co-culture with LX-2 on HCC. BMI1 overexpression promoted HCC stemness and activated PI3K/AKT pathway, which was reversed by PI3K inhibition. PAK4 was activated by KGF, then phosphorylated S315 site and promoted protein stability of BMI1, therefore enhanced HCC stemness. BMI1 also had a promote effect on liver fibrosis. In summary, we found that KGF secreted by HSCs activated PAK4, which phosphorylated S315 and promoted protein stability of BMI1, and further promoted liver fibrosis and HCC stemness through the PI3K/AKT signaling pathway. Our present study deeply studied the interaction and mechanism between HSCs and HCC, which might provide a new insight for HCC therapy.

F. Virgili, F. Acconcia, R. Ambra, A. Rinna, P. Totta, and M. Marino, “ Nutritional Flavonoids Modulate Estrogen Receptor α Signaling,” IUBMB Life 56, no. 3 (2004): 145–151, https://doi.org/10.1080/15216540410001685083.

The above article, published online on 3 January 2008 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Efstathios S. Gonos; the International Union of Biochemistry and Molecular Biology; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, duplication of several Western Blot bands has been detected within Figure 2a. The relative raw data could no longer be accessed due to the considerable time elapsed since the article's publication. The corresponding author, Maria Marino, maintains that the concerns do not impact the overall results and conclusions of the study, and disagrees with the decision of retraction. However, the article is retracted as the editors have lost trust in the integrity of the data presented and consider the conclusions invalid.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes to support protein synthesis in all organisms. Recent studies, empowered by advancements in genome sequencing, have uncovered an increasing number of disease-causing mutations in aaRSs. Monoallelic aaRS mutations typically lead to dominant peripheral neuropathies such as Charcot–Marie–Tooth (CMT) disease, whereas biallelic aaRS mutations often impair the central nervous system (CNS) and cause neurodevelopmental disorders. Here, we review recent progress in the disease onsets, molecular basis, and potential therapies for diseases caused by aaRS mutations, with a focus on biallelic mutations in cytoplasmic aaRSs.

Dasgupta A, Dey D, Ghosh D, Lai TK, Bhuvanesh N, Dolui S, Velayutham R, Acharya K. Astrakurkurone, a Sesquiterpenoid from wild edible mushroom, targets liver cancer cells by modulating Bcl-2 family proteins. IUBMB Life. 2019;71(7): 992–1002. https://doi.org/10.1002/iub.2047

An investigation based on concerns raised by a third party revealed the duplication of figure panels between Figure 3A and C, and high similarity between Figure 5B I Caspase 9 and GAPDH lanes, and 5B II Bax and Caspase 2 lanes. The authors admitted to the image compilation error in Figure 3 and were able to provide the original images of the article. The original images provided could not fully address the raised concerns, therefore the authors have repeated these experiments. The new experiments confirmed their earlier results, thus the corresponding conclusions of the paper remain unaffected. The new, corrected Figures 3 and 5 are shown as follows.

Aminoacyl-tRNA synthetases (aaRSs) are universally essential enzymes that synthesize aminoacyl-tRNA substrates for protein synthesis. Although most organisms require a single aaRS gene for each proteinogenic amino acid to translate their genetic information, numerous species encode multiple gene copies of an aaRS. Growing evidence indicates that organisms acquire extra aaRS genes to sustain or adapt to their unique lifestyle. However, predicting and defining the function of repeated aaRS genes remains challenging due to their potentially unique physiological role in the host organism and the inconsistent annotation of repeated aaRS genes in the literature. Here, we carried out comparative, phylogenetic, and functional studies to determine the activity of coexisting paralogs of tryptophanyl-, tyrosyl-, seryl-, and prolyl-tRNA synthetases encoded in several human pathogenic bacteria. Our analyses revealed that, with a few exceptions, repeated aaRSs involve paralogous genes with distinct phylogenetic backgrounds. Using a collection of Escherichia coli strains that enabled the facile characterization of aaRS activity in vivo, we found that, in almost all cases, one aaRS displayed transfer RNA (tRNA) aminoacylation activity, whereas the other was not compatible with E. coli. Together, this work illustrates the challenges of identifying, classifying, and predicting the function of aaRS paralogs and highlights the complexity of aaRS evolution. Moreover, these results provide new insights into the potential role of aaRS paralogs in the biology of several human pathogens and foundational knowledge for the investigation of the physiological role of repeated aaRS paralogs across bacteria.

The nucleotide excision repair (NER) system is one of the main ways to protect organisms from DNA damage caused by endogenous and exogenous carcinogens. NER deficiency increases genome mutations, chromosomal aberrations, and cancer viability. However, the genetic association between Wilms tumor and NER pathway gene polymorphisms needs to be further validated. We assessed the associations between 19 NER gene polymorphisms and Wilms tumor susceptibility in 416 cases and 936 controls from East China via the TaqMan method. We found that xeroderma pigmentosum group D (XPD) rs238406 and rs13181 significantly decreased the risk of Wilms tumor [adjusted odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.46–0.75, p <.0001; adjusted OR = 0.63, 95% CI = 0.44–0.89, p = .009, respectively]. Furthermore, the rs751402 and rs2296147 polymorphisms in the xeroderma pigmentosum group G (XPG) gene were significantly correlated with an increased risk for Wilms tumor (adjusted OR = 1.47, 95% CI = 1.03–2.09, p = .034; adjusted OR = 2.14, 95% CI = 1.29–3.56, p = .003, respectively). Expression quantitative trait loci (eQTL) analysis revealed that these four polymorphisms may affect the expression of genes that are adjacent to XPD and XPG. Our study provides evidence that XPD and XPG gene polymorphisms are associated with Wilms tumor risk. Nonetheless, these findings should be confirmed in a larger sample size.

Heterozygous pathogenic variants in the histidyl-tRNA synthetase (HARS) gene are associated with Charcot–Marie–Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl-tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl-tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine.

This current investigation explored the thermal conversion process of castor wood into biochar, which was subsequently harnessed for removing naproxen from pharmaceutical industrial effluent via adsorption. Surface composition analyses conducted through scanning electron microscopy–energy dispersive X-ray, laser-induced breakdown spectroscopy, and Fourier-transform infrared studies unveiled the presence of nano MgO particles within the adsorbent material. Employing optimization techniques such as response surface methodology facilitated a refined approach to batch study. The optimized conditions for batch naproxen sodium (NPX) adsorption on nano-MgO-modified biochar were identified as pH 4, 1.5 g/L adsorbent dosage, and a 120-min contact time maintaining a constant NPX concentration of 10 mg/L. The adsorption capacity was calculated to be 123.34 mg/g for a nano-magnesium oxide-modified castor wood biochar (modified biochar) and 99.874 mg/g for pristine castor wood biochar (pristine biochar). Fenton's reagents comprising 15 mM of FeSO₄ (7H₂O) and 25 mM of H₂O₂ have been scrutinized under conditions of pH 3.0, a reaction time of 30 min, a temperature of 30°C, and stirring at 120 rpm, followed by batch adsorption treatment. The COD, NH₃–N, NO₃⁻, PO₄³⁻, and NPX removal percentages was found to be 90%, 87%, 79%, 80%, and 90%, respectively. Thus nano MgO-modified biochar holds promise of treatment of pharmaceutical effluent.

Mutant epidermal growth factor receptor (EGFR) signaling has emerged as a key cause of carcinogenesis and therapy resistance in non-small cell lung cancer (NSCLC), which continues to pose a serious threat to world health. In this study, we aimed to elucidate the complex molecular pathways of EGFR-mediated autophagy signaling in NSCLC. We identified naphtho[2,3-a]pyrene, an anthraquinolone derivative, to be a promising investigational drug that targets EGFR-mediated autophagy using a cellular model system. By utilizing systems biology, we developed a computational model that explained the signaling of EGFR-mediated autophagy and identified critical crosstalk sites that could be inhibited therapeutically. As a lead compound, naphtho[2,3-a]pyrene was confirmed by molecular docking experiments. It was found to be cytotoxic to NSCLC cells, impact migration, induce apoptosis, and arrest cell cycle, both on its own and when combined with standard drugs. The anticancer efficacy of naphtho[2,3-a]pyrene was validated in vivo on CDX nude mice. It showed synergistic activity against NSCLC when coupled with gefitinib, chloroquine, and radiation. Altogether, our study highlights naphtho[2,3-a]pyrene's therapeutic promise in NSCLC by focusing on EGFR-mediated autophagy and providing a new strategy to fight drug resistance and tumor survival.