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Biomolecules Jun 2024Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some...
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
Topics: Multiple Myeloma; Humans; Thalidomide; Drug Resistance, Neoplasm; Antineoplastic Agents; Angiogenesis Inhibitors; Cell Line, Tumor; Anti-Inflammatory Agents; Drug Evaluation, Preclinical
PubMed: 38927128
DOI: 10.3390/biom14060725 -
Biomolecules Jun 2024(1) Background: Phytochemicals are crucial antioxidants that play a significant role in preventing cancer. (2) Methods: We explored the use of methyl jasmonate (MeJA) in...
(1) Background: Phytochemicals are crucial antioxidants that play a significant role in preventing cancer. (2) Methods: We explored the use of methyl jasmonate (MeJA) in the in vitro cultivation of adventitious roots (DMAR) and evaluated its impact on secondary metabolite production in DMAR, optimizing concentration and exposure time for cost-effectiveness. We also assessed its anti-inflammatory and anti-lung cancer activities and related gene expression levels. (3) Results: MeJA treatment significantly increased the production of the phenolic compound 3,5-Di-caffeoylquinic acid (3,5-DCQA). The maximum 3,5-DCQA production was achieved with a MeJA treatment at 40 µM for 36 h. MeJA-DMARE displayed exceptional anti-inflammatory activity by inhibiting the production of nitric oxide (NO) and reactive oxygen species (ROS) in LPS-induced RAW 264.7 cells. Moreover, it downregulated the mRNA expression of key inflammation-related cytokines. Additionally, MeJA-DMARE exhibited anti-lung cancer activity by promoting ROS production in A549 lung cancer cells and inhibiting its migration. It also modulated apoptosis in lung cancer cells via the Bcl-2 and p38 MAPK pathways. (4) Conclusions: MeJA-treated DMARE with increased 3,5-DCQA production holds significant promise as a sustainable and novel material for pharmaceutical applications thanks to its potent antioxidant, anti-inflammatory, and anti-lung cancer properties.
Topics: Cyclopentanes; Oxylipins; Acetates; Animals; Mice; Anti-Inflammatory Agents; Lung Neoplasms; Humans; RAW 264.7 Cells; Plant Roots; Reactive Oxygen Species; Nitric Oxide; Apoptosis; Quinic Acid; A549 Cells; Sapindaceae
PubMed: 38927108
DOI: 10.3390/biom14060705 -
Biomolecules Jun 2024The antioxidant defense mechanisms play a critical role in mitigating the deleterious effects of reactive oxygen species (ROS). Catalase stands out as a paramount... (Review)
Review
The antioxidant defense mechanisms play a critical role in mitigating the deleterious effects of reactive oxygen species (ROS). Catalase stands out as a paramount enzymatic antioxidant. It efficiently catalyzes the decomposition of hydrogen peroxide (HO) into water and oxygen, a potentially harmful byproduct of cellular metabolism. This reaction detoxifies HO and prevents oxidative damage. Catalase has been extensively studied as a therapeutic antioxidant. Its applications range from direct supplementation in conditions characterized by oxidative stress to gene therapy approaches to enhance endogenous catalase activity. The enzyme's stability, bioavailability, and the specificity of its delivery to target tissues are significant hurdles. Furthermore, studies employing conventional catalase formulations often face issues related to enzyme purity, activity, and longevity in the biological milieu. Addressing these challenges necessitates rigorous scientific inquiry and well-designed clinical trials. Such trials must be underpinned by sound experimental designs, incorporating advanced catalase formulations or novel delivery systems that can overcome existing limitations. Enhancing catalase's stability, specificity, and longevity in vivo could unlock its full therapeutic potential. It is necessary to understand the role of catalase in disease-specific contexts, paving the way for precision antioxidant therapy that could significantly impact the treatment of diseases associated with oxidative stress.
Topics: Catalase; Humans; Oxidative Stress; Animals; Antioxidants; Reactive Oxygen Species; Hydrogen Peroxide; Genetic Therapy
PubMed: 38927099
DOI: 10.3390/biom14060697 -
Biomolecules Jun 2024Ubiquitin-specific protease 5 (USP5) belongs to the ubiquitin-specific protease (USP) family, which uniquely recognizes unanchored polyubiquitin chains to maintain the... (Review)
Review
Ubiquitin-specific protease 5 (USP5) belongs to the ubiquitin-specific protease (USP) family, which uniquely recognizes unanchored polyubiquitin chains to maintain the homeostasis of monoubiquitin chains. USP5 participates in a wide range of cellular processes by specifically cleaving isopeptide bonds between ubiquitin and substrate proteins or ubiquitin itself. In the process of immune regulation, USP5 affects important cellular signaling pathways, such as NF-κB, Wnt/β-catenin, and IFN, by regulating ubiquitin-dependent protein degradation. These pathways play important roles in immune regulation and inflammatory responses. In addition, USP5 regulates the activity and function of immunomodulatory signaling pathways via the deubiquitination of key proteins, thereby affecting the activity of immune cells and the regulation of immune responses. In the present review, the structure and function of USP5, its role in immune regulation, and the mechanism by which USP5 affects the development of diseases by regulating immune signaling pathways are comprehensively overviewed. In addition, we also introduce the latest research progress of targeting USP5 in the treatment of related diseases, calling for an interdisciplinary approach to explore the therapeutic potential of targeting USP5 in immune regulation.
Topics: Humans; Animals; Signal Transduction; Endopeptidases; Ubiquitination; Immunomodulation
PubMed: 38927085
DOI: 10.3390/biom14060683 -
Biomolecules May 2024Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected...
Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner-Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.
Topics: Humans; Gastrointestinal Microbiome; Tryptophan; Renal Dialysis; Indoles; Male; Female; Middle Aged; Aged; Kidney Failure, Chronic; Feces; Metabolic Networks and Pathways; Adult; Metagenome
PubMed: 38927027
DOI: 10.3390/biom14060623 -
Biomolecules May 2024Gastric cancer (GC) ranks as the third most prevalent malignancy and a leading cause of cancer-related mortality worldwide. However, the majority of patients with GC are... (Review)
Review
Gastric cancer (GC) ranks as the third most prevalent malignancy and a leading cause of cancer-related mortality worldwide. However, the majority of patients with GC are diagnosed at an advanced stage, highlighting the urgent need for effective perioperative and postoperative chemotherapy to prevent relapse and metastasis. The current treatment strategies have limited overall efficacy because of intrinsic or acquired drug resistance. Recent evidence suggests that dysregulated long non-coding RNAs (lncRNAs) play a significant role in mediating drug resistance in GC. Therefore, there is an imperative to explore novel molecular mechanisms underlying drug resistance in order to overcome this challenging issue. With advancements in deep transcriptome sequencing technology, lncRNAs-once considered transcriptional noise-have garnered widespread attention as potential regulators of carcinogenesis, including tumor cell proliferation, metastasis, and sensitivity to chemo- or radiotherapy through multiple regulatory mechanisms. In light of these findings, we aim to review the mechanisms by which lncRNAs contribute to drug therapy resistance in GC with the goal of providing new insights and breakthroughs toward overcoming this formidable obstacle.
Topics: Humans; Stomach Neoplasms; RNA, Long Noncoding; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Antineoplastic Agents; Animals
PubMed: 38927012
DOI: 10.3390/biom14060608 -
BMC Emergency Medicine Jun 2024A severely injured patient needs fast transportation to a hospital that can provide definitive care. In Norway, approximately 20% of the population live in rural areas....
BACKGROUND
A severely injured patient needs fast transportation to a hospital that can provide definitive care. In Norway, approximately 20% of the population live in rural areas. Primary care doctors (PCDs) play an important role in prehospital trauma care. The aim of this study was to investigate how variations in PCD call-outs to severe trauma incidents in Norway were associated with rural-urban settings and time factors.
METHODS
In this study on severe trauma patients admitted to Norwegian hospitals from 2012 to 2018, we linked data from four official Norwegian registries. Through this, we investigated the call-out responses of PCDs to severe trauma incidents. In multivariable log-binomial regression models, we investigated whether factors related to rural-urban settings and time factors were associated with PCD call-outs.
RESULTS
There was a significantly higher probability of PCD call-outs to severe trauma incidents in the municipalities in the four most rural centrality categories compared to the most urban category. The largest difference in adjusted relative risk (95% confidence interval (CI)) was 2.08 (1.27-3.41) for centrality category four. PCDs had a significantly higher proportion of call-outs in the Western (RR = 1.46 (1.23-1.73)) and Central Norway (RR = 1.30 (1.08-1.58)) Regional Health Authority areas compared to in the South-Eastern area. We observed a large variation (0.47 to 4.71) in call-out rates to severe trauma incidents per 100,000 inhabitants per year across the 16 Emergency Medical Communication Centre areas in Norway.
CONCLUSIONS
Centrality affects the proportion of PCD call-outs to severe trauma incidents, and call-out rates were higher in rural than in urban areas. We found no significant difference in call-out rates according to time factors. Possible consequences of these findings should be further investigated.
Topics: Humans; Norway; Male; Female; Wounds and Injuries; Adult; Middle Aged; Time Factors; Physicians, Primary Care; Registries; Aged; Emergency Medical Services; Rural Health Services; Rural Population; Adolescent; Young Adult
PubMed: 38926855
DOI: 10.1186/s12873-024-01027-5 -
Immunity & Ageing : I & A Jun 2024The aging process intricately involves immune system dynamics, with a crucial role in managing senescent cells (SNCs) and their senescence-associated secretory... (Review)
Review
The aging process intricately involves immune system dynamics, with a crucial role in managing senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Unfortunately, immunosenescence, a progressively dysregulated immunity with age, hampers effective SNC elimination, leading to accumulation, coupled with the release of SASPs, which, in turn, inhibits immunity and heightened susceptibility to aging-associated diseases (AADs). Natural killer (NK) cells, integral to the innate immune system, play a pivotal role in addressing SNCs swiftly. These cells also coordinate with other components of both innate and adaptive immunity to surveil and eliminate these cells. Accordingly, preserving NK cell function during aging is crucial for evading AADs and promoting healthy aging. Alternatively, NK-cell-based therapies present promising avenues for addressing the challenges associated with aging. Notable, recent studies in adoptive NK cell therapy have shown promise in rejuvenating immunosenescence, eliminating SNCs, and alleviating SASPs. This progress provides the proof-concept of adoptive NK cell therapy for senotherapy and holds promise as an emerging revolution in longevity therapeutics.
PubMed: 38926847
DOI: 10.1186/s12979-024-00451-2 -
Genomics & Informatics Jun 2024Cervical cancer (CxCa) stands as a significant global health challenge, ranking fourth in cancer-related mortality among the female population. While chemotherapy...
OBJECTIVE
Cervical cancer (CxCa) stands as a significant global health challenge, ranking fourth in cancer-related mortality among the female population. While chemotherapy regimens have demonstrated incremental progress in extending overall survival, the outlook for recurrent CxCa patients remains disheartening. An imperative necessity arises to delve into innovative therapeutic avenues, with molecular targeted therapy emerging as a promising candidate. Previous investigations have shed light on the therapeutic effectiveness of five distinct herbal compounds, epicatechin, curcumin, myricetin, jatrorrhizine, and arborinine, within the context of CxCa.
METHODS
A systems biology approach was employed to discern differentially expressed genes (DEGs) in CxCa tissues relative to healthy cervical epithelial tissues. A protein-protein interaction network (PPIN) was constructed, anchored in the genes related to CxCa. The central genes were discerned within the PPIN, and Kaplan-Meier survival curves explored their prognostic significance. An assessment of the binding affinity of the selected herbal compounds to the master regulator of prognostic markers in CxCa was conducted.
RESULTS
A significant correlation between the overexpression of MYC, IL6, JUN, RRM2, and VEGFA and an adverse prognosis in CxCa was indicated. The regulation of these markers is notably influenced by the transcription factor CEBPD. Molecular docking analysis indicated that the binding affinity between myricetin and the CEBPD DNA binding site was robust.
CONCLUSION
The findings presented herein have unveiled pivotal genes and pathways that play a central role in the malignant transformation of CxCa. CEBPD has emerged as a potential target for harnessing the therapeutic potential of myricetin in this context.
PubMed: 38926832
DOI: 10.1186/s44342-024-00008-1 -
Trends in Genetics : TIG Jun 2024The dark genome, the nonprotein-coding part of the genome, is replete with long noncoding RNAs (lncRNAs). These functionally versatile transcripts, with specific... (Review)
Review
The dark genome, the nonprotein-coding part of the genome, is replete with long noncoding RNAs (lncRNAs). These functionally versatile transcripts, with specific temporal and spatial expression patterns, are critical gene regulators that play essential roles in health and disease. In recent years, FAAH-OUT was identified as the first lncRNA associated with an inherited human pain insensitivity disorder. Several other lncRNAs have also been studied for their contribution to chronic pain and genome-wide association studies are frequently identifying single nucleotide polymorphisms that map to lncRNAs. For a long time overlooked, lncRNAs are coming out of the dark and into the light as major players in human pain pathways and as potential targets for new RNA-based analgesic medicines.
PubMed: 38926010
DOI: 10.1016/j.tig.2024.04.009