Search

Background: Multiple Myeloma (MM) is the second most common hematological malignancy, characterized by the accumulation of monoclonal plasmocytes in the bone marrow. Despite advancements with proteasome inhibitors, immunomodulatory agents, and CD38-targeting antibodies, MM remains largely incurable due to resistant clones and frequent relapses. The success of the proteasome inhibitor bortezomib (BTZ) in MM treatment highlights the critical role of the ubiquitin-proteasome system (UPS) in this disease. Deubiquitinases (DUBs), which regulate protein stability, interactions, and localization by removing ubiquitin modifications, have emerged as promising therapeutic targets in various cancers, including MM., Methods: Through a comprehensive loss-of-function screen, we identified USP39 as a critical survival factor for MM cells. Gene Set Enrichment Analysis (GSEA) was employed to correlate USP39 mRNA levels with clinical outcomes in MM patients. USP39 protein expression was evaluated via immunohistochemistry (IHC) on bone marrow samples from MM patients and healthy controls. The impact of USP39 knockdown via SiRNA was assessed through in vitro assays measuring cellular metabolism, clonogenic capacity, cell cycle progression, apoptosis, and sensitivity to BTZ. Co-immunoprecipitation and deubiquitination assays were conducted to elucidate the interaction and regulation of ZEB1 by USP39. Finally, in vitro and in vivo zebrafish experiments were used to characterize the biological consequences of ZEB1 regulation by USP39., Results: Our study found that elevated USP39 mRNA levels are directly associated with shorter survival in MM patients. USP39 protein expression is significantly higher in MM patient plasmocytes compared to healthy individuals. USP39 knockdown inhibits clonogenic capacity, induces cell cycle arrest, triggers apoptosis, and overcomes BTZ resistance. Gain-of-function assays revealed that USP39 stabilizes the transcription factor ZEB1, enhancing the proliferation and the trans-migratory potential of MM cells., Conclusions: Our findings highlight the critical role of the deubiquitinase USP39, suggesting that the USP39/ZEB1 axis could serve as a potential diagnostic marker and therapeutic target in MM., Competing Interests: Declarations. Ethics approval and consent to participate: All Zebrafish experiments were approved by the IRCAN Experimental Animal Ethical Committee. Consent for publication: All authors consent to publication. Competing interests: The authors have declared that no competing interests exist., (© 2024. The Author(s).)

Modulation of nociception allows animals to optimize chances of survival by adapting their behaviour in different contexts. In mammals, this is executed by neurons from the brain and is referred to as the descending control of nociception. Whether insects have such control, or the neural circuits allowing it, has rarely been explored. Based on behavioural, neuroscientific and molecular evidence, we argue that insects probably have descending controls for nociception. Behavioural work shows that insects can modulate nocifensive behaviour. Such modulation is at least in part controlled by the central nervous system since the information mediating such prioritization is processed by the brain. Central nervous system control of nociception is further supported by neuroanatomical and neurobiological evidence showing that the insect brain can facilitate or suppress nocifensive behaviour, and by molecular studies revealing pathways involved in the inhibition of nocifensive behaviour both peripherally and centrally. Insects lack the endogenous opioid peptides and their receptors that contribute to mammalian descending nociception controls, so we discuss likely alternative molecular mechanisms for the insect descending nociception controls. We discuss what the existence of descending control of nociception in insects may reveal about pain perception in insects and finally consider the ethical implications of these novel findings.

Aims: Lung cancer is the leading cause of cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung tumor development. We analyzed the effect of tobacco-specific nitrosamines (TSNAs) on human lung adenocarcinoma metabolic reprogramming, an emergent hallmark of carcinogenesis. Results: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic, and tumor biology studies were performed to analyze changes in lung cancer cell metabolism and the consequences for hallmarks of cancer, including tumor growth, cancer cell invasion, and redox signaling. The findings revealed that nicotine-derived nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung tumor growth in vivo . These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the beta-2 adrenergic receptors (β2-AR)-cholinergic receptor nicotinic alpha 7 subunit (CHRNAα7)-dependent nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial reactive oxygen species and Annexin A1 in tumor growth promotion. Conversely, ectopic expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in lung cancer. Innovation: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes lung cancer. Conclusion: Mitochondria play a role in the promotion of lung cancer induced by tobacco-specific nitrosamines. Antioxid. Redox Signal. 36, 525-549.

This study compared the effects dietary organic (ferrous glycine [FG]) versus inorganic (ferrous sulfate [FS]) iron in laying hens on performance, egg quality, serum and egg yolk lipids, antioxidant status, and iron enrichment of eggs. A total of 378 Shaver White layers were allotted to 7 treatments with 6 replicates (9 birds each) from 30 to 42 weeks of age. A basal diet (19 mg iron/kg) served as control, while the other six diets were supplemented with either FS or FG to provide 30, 60, and 120 mg/kg of added iron. Dietary FG and FS treatments improved (P < 0.05) laying rate, egg weight, and egg quality of layers, relative to the control, albeit eggshell strength and eggshell calcium also deteriorated with the highest level of FS (P < 0.05). The iron treatment groups exhibited a lower serum and egg yolk levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol that accompanied by higher levels of high-density lipoprotein cholesterol and greater activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) as compared with the control (P < 0.05). The contents of malondialdehyde and protein carbonyl were conversely related to the activities SOD and GPx (P < 0.05). The serum and egg fractions (yolk, albumen, and shell) displayed gradually increases in iron contents as the level of iron increased in the diet (P < 0.05), while FG was superior to FS at all tested levels (P < 0.05). To summary, FS can be replaced by FG, with more favorable impacts on egg quality and iron enrichment.

Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.

Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo . Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling.

Metabolic reprogramming is a hallmark of cancer and the link between oncogenes activation, tumor supressors inactivation and bioenergetics modulation is well established. However, numerous carcinogenic environmental factors are responsible for early cancer initiation and their impact on metabolic reprogramming just starts to be deciphered. For instance, it was recently shown that UVB irradiation triggers metabolic reprogramming at the pre-cancer stage with implication for skin cancer detection and therapy. These observations foster the need to study the early changes in tissue metabolism following exposure to other carcinogenic events. According to the International Agency for Research on Cancer (IARC), tobacco smoke is a major class I-carcinogenic environmental factor that contains different carcinogens, but little is known on the impact of tobacco smoke on tissue metabolism and its participation to cancer initiation. In particular, tobacco-specific nitrosamines (TSNAs) play a central role in tobacco-smoke mediated cancer initiation. Here we describe the recent advances that have led to a new hypothesis regarding the link between nitrosamines signaling and metabolic reprogramming in cancer., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.

The human epidermal growth factor 2 (HER2) gene undergoes various mutations that could alter its activity or respond to the antibody therapies. Cetuximab, a known anti-EGFR monoclonal antibody (mAB), is widely administered in metastatic colorectal cancer (mCRC) cases. Here we identified mCRC patients who did not respond to cetuximab (500 mg/m 2 , q2w) after fluoropyrimidine/oxaliplatin regimen failure. Tumor samples were examined with immunohistochemistry for protein distribution, polymerase chain reaction (PCR) sequencing for mutation detection and real-time PCR for mRNA expression pattern analysis between cetuximab sensitive and resistance patients. The conformational differences of normal and mutated protein structures were predicted by bioinformatics analysis. The 5-year survival rates of target groups were estimated using the Kaplan-Meier method. Immunohistochemistry showed that all cases had high level of HER2 protein. No K-Ras or B-Raf mutation was observed among the study population; however, cetuximab resistance patients harbored a somatic mutation R784G at the exon 20 region of HER2 coding sequence. According to bioinformatics analysis, this mutation caused a notable misfold in protein conformation. Meanwhile, survival analysis showed R784G mutated mCRC patients had shortened survival rate compared with the mCRC cases with wild-type HER2. Collectively, these data report a new mechanism of resistance to cetuximab and might be applicable in modifying new therapeutic strategies for HER2 involved cancers., (© 2018 Wiley Periodicals, Inc.)

Background: Epidural anesthesia (EA) today has been used extensively in surgical procedures and the management of pain associated with midwifery and chronic pain. This type of anesthesia can be done in different technical, physiological, and pharmacological ways. The aim of this study was to compare the effects of thoracic EA with general anesthesia (GA) on hemodynamic changes and its complications in patients underwent laparoscopic colonoscopy., Materials and Methods: This clinical trial study was conducted on 80 patients undergoing laparoscopic cholecystectomy with EA or GA based on inclusion and exclusion criteria. The patients were randomly divided into two groups of 40 and changes in blood pressure, systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and arterial blood oxygen saturation were measured. The incidence of nausea, vomiting, chills, and itching in the two groups was recorded. The analysis was performed descriptively and also using t -test and Chi-square tests., Results: The results showed that the mean of SBP and DBP, HR, and arterial blood oxygen saturation and the incidence of nausea and vomiting was statistically significant ( P < 0.05) between the two groups at 4, 6, and 12 h after anesthesia and it was higher in a group of GA. There was no significant difference in shivering and itching between the two groups ( P > 0.05)., Conclusion: The results of this study indicated that thoracic EA in patients with laparoscopic cholecystectomy has significant effects on factors such as SBP and DBP and arterial blood oxygen saturation. Furthermore, EA has fewer complications than GA, and it is the preferable approach., Competing Interests: There are no conflicts of interest.

Background: The Molavi street archeological site south of Tehran accidentally provided a unique opportunity for paleoparasitological studies in Iran. A female skeleton was unearthed and evaluated to be 7000 years old. Soil samples were collected around the pelvic and sacrum bones., Findings: Careful microscopic investigation of rehydrated soil samples revealed the presence of one Enterobius vermicularis egg attached to the skeleton sacral region., Conclusion: The present finding likely represents the oldest evidence of a human pinworm infection in Asia.