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Biomolecular condensates (BCs), including membraneless organelles, are basically Ribonucleic acid (RNA)-protein complexes that are emerging as a potential candidate because of its paramount significance in revealing fundamentals of cell biology and pathology including cancer. Aiming to understand its importance, scientists are dealing with it in an interdisciplinary manner—from polymer chemistry to genetics. Over time the mechanism of liquid-liquid phase separation (LLPS) and the model of ‘Stickers and Spacers’ have widened our understanding and broadened our scope of approaches to get insights into these molecular entities. RNA molecules and its specific partner proteins, certain ribonucleoproteins (RNPs), play pivotal roles in different trajectories of BCs, i.e., in localization, compartmentalization, epigenetic regulation, and dynamics. However, several aspects need to be made clearer to tackle human diseases including cancer. In addition to the RNAs, in this review specific aspects of the BCs are presented in the context of neurodegenerative diseases, viral infections and cancer, and their link with stress granules (SG), P bodies, paraspeckles, and host encoded and viral encoded non-coding RNAs, discussing cancer associated proteins, tumour suppressors and repressors, dysregulation of cancer signals, and role of super enhancers. A special focus is reserved to oncolytic viruses and epidemic viruses, through the intervention on stress granule protein partners, virus-formed intracellular condensates, and viral RNAs. The review covers not only the basics of BCs but also encompasses the emerging context of condensate-targeted drug discovery and cancer therapeutics by means of Proteolysis-targeting chimera (PROTAC), Ribonuclease-targeting chimera (RIBOTAC), small molecule inhibitors of protein-RNA interactions, Antisense oligonucleotides (ASO) and compounds targeting non-coding RNA (ncRNA) triple helix, determining RNA degradation.
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The significant role of tobacco smoking as a primary risk factor for respiratory diseases has been extensively substantiated. In addition, cannabis use has been linked to persistent respiratory symptoms and numerous lung disorders in several case studies. Tetrahydrocannabinol (THC), the major active principle in all cannabis products, exerts its effects by binding to cannabinoid type 1 (CB1) receptors and, to a lesser extent, cannabinoid type 2 (CB2) receptors, which are differentially expressed in both the central and peripheral nervous systems, as well as other anatomical systems, including the respiratory one. Research conducted to date has enabled a comprehensive understanding of the mechanisms involved in cigarette smoking and its role in the development of chronic respiratory conditions. Recent investigations have also postulated that smoking cannabis may increase the risk of airway obstruction. This review focuses on fully understanding the impact of cigarette smoke extract (CSE) and THC on the human respiratory mucosa by using a methodological approach to assess the administration techniques and experimental models used in this field. Traditional single-layer cell cultures are a cost-effective research solution. However, they fail to replicate the complex structure and function of human organs' microenvironments in vivo. Therefore, after analysing various experimental models proposed in the literature, we concluded that the three-dimensional ex vivo culture model could be considered the most suitable one for studying the effects of CSE and THC on the respiratory mucosa.
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A variety of events, including infection, traumatic brain damage, neurodegenerative illnesses, and autoimmune disorders, can cause neuroinflammation, a complicated biological reaction in the central nervous system. Glial cells, especially microglia and astrocytes, are activated as part of this complex event, which also results in the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. In this review, the role of microglia and astrocytes in neuroinflammation, as well as the important neuroinflammatory factors including their pathways, and positive and negative aspects of neuroinflammation are discussed. It was earlier documented that microglial cells and astrocytes play a notable role in immune and inflammatory diseases. Various pro-apoptotic pathways like nuclear factor kappa B (NF-κB), cytokines, cyclooxygenases, reactive oxygen species (ROS), and mitogen-activated protein kinase (MAPK) are responsible for the induction of neuroinflammation. Neuroinflammation may also lead to many neurodegenerative diseases like Alzheimer's disease, multiple sclerosis, and Parkinson's disease. It has also been reported that inflammasomes and multi-protein oligomers are also responsible for neuroinflammation.
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Background: Migraine is one of the most common neurological disorders occurring globally and its treatment is currently based on synthetic drugs. Due to undesired effects associated with these agents, some of the patients might prefer natural compounds-based therapies that are cost-effective, efficacious, have more patient compliance and less adverse effects. Hence, this systematic review was conducted to evaluate the effects of natural compounds (single/combination) used for the prophylaxis or acute treatment of migraine.
Method: Five electronic databases (PubMed, Scopus, Cochrane Library, Cumulated Index to Nursing and Allied Health Literature (CINAHL) library and Web of Science) were searched from 1 March 2020–31 January 2024. We included studies that evaluated the effects of natural compounds on migraine through randomized clinical trials (RCTs) that reported the duration of migraine headache, severity and frequency of attacks as primary outcomes. Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist was used to report the study while Cochrane Collaboration's Risk of Bias (ROB) 2 tool was used to assess the ROB in included studies. The review protocol was registered on PROSPERO (CRD42023454998).
Results: Twelve RCTs with 889 participants were included. Seven RCTs had low ROB and two RCTs had high ROB, while three RCTs expressed “some concerns”. It was observed that natural compounds including curcumin, topical basil, cinnamon, ginger, Vitamin D3 (Vit D3), zinc (Zn), magnesium (Mg) and cobalamin significantly reduced the severity of migraine headache. In addition, the duration of migraine attacks was significantly decreased by curcumin, cinnamon, ginger, Vit D3, Mg and cobalamin. Further, curcumin, topical basil, cinnamon, Vit D3, Zn, Mg and cobalamin exhibited significant beneficial effect on migraine frequency. In contrast, nanocurcumin and jodeungsan showed no significant results.
Conclusion: The current findings suggest that natural compounds including cinnamon, Vit D3, Zn, Mg and cobalamin might mitigate migraine attacks and serve as interesting alternate therapies. Nonetheless, further large scale studies are highly desired.
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Background: Differentiated Thyroid Carcinoma (DTC) presents diverse patient outcomes, highlighting the need to identify reliable prognostic biomarkers. This study focuses on the role of interleukins, particularly interleukin18 (IL18), in predicting survival rates and treatment responses among DTC patients.
Methods: We conducted a comprehensive analysis of the association between various pyroptosis-related genes (IL18, IL1A, IL6, Granzyme A (GZMA), and Neutrophil elastase (ELANE)) and overall survival in DTC. The study employed univariate and multivariate Cox models to assess the prognostic value of these cytokines. Additionally, a nomogram model was created, integrating clinical characteristics to improve the precision of predicting patient outcomes. IL18 expression levels in DTC tissues compared to normal tissues were examined, along with their association with patient survival and response to radioactive iodine (RAI) therapy.
Results: IL18 emerged as a significant protective factor associated with better survival outcomes, exhibiting higher expression levels in DTC tissues compared to normal tissues. However, its expression was notably lower in RAI-refractory or high-risk groups. This study also identified axitinib as a potential therapeutic agent for high-risk DTC cases, supported by drug prediction analysis. Furthermore, immune cell analysis linked high IL18 expression with an abundance of specific T cells, indicating its involvement in regulating the immune response and influencing the effectiveness of RAI treatment.
Conclusions: IL18 holds promise as a prognostic biomarker in DTC, offering valuable insights into patient survival and potential treatment pathways. This study emphasizes the importance of combining molecular and clinical data to improve prognostic models and therapeutic strategies, highlighting the need for further research into the mechanisms of action of IL18 in DTC.
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Background: Prostate cancer (PC) is one of the most common malignant tumors, and the effect of celastrol on squalene synthase (SQS) in PC is unknown. This study aimed to investigate the effect of celastrol on SQS in PC.
Methods: The protein expression was detected by Western blot. Cell proliferation capacity was detected by cell counting kit-8 (CCK-8) kit (450 nm optical density values). Cell scratch (wounding healing rate) and transwell assays (migration cells number) detected the cells' migration abilities. Messenger RNA (mRNA) expression was detected using a real-time polymerase chain reaction test.
Results: Celastrol decreased the expression of SQS in PC cells, and the knockdown of the SQS-encoding gene farnesyl-diphosphate farnesyltransferase 1 (fdft1) with and without celastrol treatment decreased PC cell proliferation and migration abilities. Furthermore, overexpression of the fdft1 gene attenuated the proliferation and migration abilities of PC-3 cells. Treatment with celastrol with fdft1 gene overexpression can still decrease the proliferation and migration abilities of PC-3 cells.
Conclusion: This study verified that celastrol decreases the proliferation and migration abilities of PC-3 and Lymph Node Carcinoma of the prostate (LNCaP) cells and revealed that celastrol reduces SQS expression. The results indicate that the inhibitory effect of celastrol on the malignant phenotypes of PC cells is partly dependent on SQS, and SQS is involved in the malignant behaviour of PC cells. Furthermore, there may be a dual effect dependent on the SQS protein expression level on the malignant phenotypes of PC cells.
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Background: Immune dysregulation is one of the hypotheses brought up to explain autism spectrum disorder (ASD). Interleukine-17A (IL-17A), a proinflammatory cytokine, has been demonstrated to be a major mediator of immune-related neurodevelopmental impairment of social behavior, including ASD. Chrysin (CHN) is a naturally occurring hydroxylated flavonoid with antioxidant, anti-inflammatory, anti-asthmatic, anticancer, cardioprotective, and neuroprotective activities. The current study investigated the effects of CHN against Polyinosinic:polycytidylic acid (Poly (I:C))-induced autism-like behavior by modulating the fetal serotonin and IL-17A levels in fetal and offspring brains in C57BL/6J mice.
Methods: Pregnant C57BL/6J mice (n = 6) were randomly selected. After the confirmation of pregnancy, female mice were divided into two different experimental groups (n = 3 female/group = 4–8 littermates/group). The pups were randomly divided into 5 experimental groups, namely, control (group I), Poly (I:C) (group II), CHN25 (group III) & CHN50 (group IV), and fluoxetine (group V). Group I and II pregnant mice were pre-treated orally with saline for 12 consecutive days (Estrus Day 0.5 (E0.5) to E12.5) and then challenged with saline (group I) and Poly (I:C) [20 mg/kg Body Weight (BW)] (group II) intraperitoneally on the 12th day (E12.5). Group III, IV & V pregnant mice were administered orally with CHN (25 mg/kg & 50 mg/kg BW) and fluoxetine (10 mg/kg, BW), respectively, for 12 consecutive days (E0.5 to E12.5) and then challenged with Poly (I:C) (20 mg/kg BW) intraperitoneally on 12th day (E12.5). In one set of studies, 1 pregnant mouse from each group was sacrificed after 4 h of Poly (I:C) injection to measure the fetal 5-Hydroxytrptophane (5-HT) and IL-17A levels in fetal brains using enzyme-linked immunosorbent assay (ELISA) kits. In the second set of experiments, the remaining pregnant mice were allowed to deliver the pups. Offspring were subjected to different behavior tests, including marble burying test (MBT), rotarod test, social interaction test (SIT) and sucrose preference test (SPT) at the age of 6, 7 and 12 weeks to investigate the autistic-like behaviors and associated symptoms. Following behavioral studies, the mice were sacrificed to isolate the prefrontal cortex (PFC), hippocampus (HC) and amygdala (AMG) tissues to measure the IL-17A levels through an ELISA kit.
Results: The findings of the present study demonstrated that Poly (I:C) administration to pregnant mice resulted in maternal immune activation (MIA), as evidenced by the significant increase in IL-17A (p < 0.05) and decrease in 5-HT levels (p < 0.001) in fetal brains. Pre-treatment of CHN and fluoxetine altered the fetal 5-HT and IL-17A levels significantly (p < 0.001). Offspring of Poly (I:C) injected pregnant mice showed autistic-like behaviors and associated symptoms as evidenced by an increased number of marbles buried in MBT and decreased fall in time in the Rotarod test, sucrose preference in SPT, and social preference in SIT significantly (p < 0.001) which were ameliorated by the chronic pre-treatment of CHN (both the dosages i.e., 25 & 50 mg) and fluoxetine significantly (p < 0.001). Further, results showed the significant elevation of IL-17A levels in PFC (p < 0.001), HC (p < 0.001) and AMG (p < 0.05) of offspring of Poly (I:C) injected pregnant mice, which were attenuated significantly by the chronic pre-treatment of CHN (both the dosage i.e., 25 & 50 mg) and fluoxetine (p < 0.001).
Conclusion: Findings of the study demonstrated that chronic pre-treatment of CHN attenuated autistic-like behavior by altering fetal 5-HT and IL-17A in fetal brain, PFC, HC, and AMG of offspring of MIA pregnant C57BL/6J mice. However, further investigation is required to establish the therapeutic applicability of CHN in ASD.
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Background: Zinc finger (ZNF) proteins play pivotal roles in the initiation, progression, and metastasis of various cancer types. Nevertheless, the precise mechanism of ZNF genes (ZNFGs) in the prognosis and treatment of gastric cancer (GC) patients remains unclear.
Methods: Transcriptomic data and clinical information related to GC, as well as ZNFG-related data, were retrieved from publicly available databases. Initially, differentially expressed ZNFGs (DE-ZNFGs) were identified through comparative analysis between GC and normal tissue samples. Subsequently, univariate and multivariate regression analyses, and the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm were utilized to identify potential biomarkers and formulate a risk assessment model. Furthermore, Kaplan-Meier survival curve analysis was conducted to analyze the correlation between the risk score and overall survival of GC patients, while the receiver operating characteristic (ROC) curve analysis was performed to evaluate the reliability of the model. Moreover, Gene Set Enrichment Analysis (GSEA) was performed to elucidate Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, comprehensive investigations were conducted to assess immune infiltration, immune checkpoints, and the immunophenoscore of distinct risk groups.
Results: A total of 165 DE-ZNFGs were identified, from which, five genes (zinc finger protein 36 (ZFP36), zinc finger protein 121 (ZNF121), ZNF131, ZNF22, and Replication initiator 1 (REPIN1) were selected as biomarkers to construct the risk model. This model demonstrated high predictive accuracy for the prognosis of GC patients, with an area under the curve (AUC) exceeding 0.6 for 1-, 3- and 5-year survival rates. Both the risk score and patient age were observed to independently predict prognosis in GC. Moreover, GSEA results showed that high risk group exhibited enrichment in pathways related to mitogen-activated protein kinase (MAPK), calcium signaling, neuroregulation, cellular connections, and cytoskeletal regulation, while low risk group was characterized by pathways associated with metabolic processes, transcription of genetic information, and stringent regulation of genetic stability. Immune analysis revealed significantly elevated stromal, immune, and Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) composite scores in high-risk patients. Additionally, there was a notable difference in the expression levels of 19 immune cells and 13 immune checkpoints between the two groups, suggesting significant immunological differences.
Conclusions: Our ZNFG-related risk model can be used to predict the survival of GC patients and may have potential guiding implications for GC treatment.
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Background: The role of Recombinant Nucleophosmin 1 (NPM1) in the development of lung adenocarcinoma (LUAD) has been recognized, however, the precise mechanism underlying this involvement remains unclear. Therefore, this study aimed to assess the mechanism of NPM1 in LUAD progression.
Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting assays were used to detect the expression level of NPM1. Furthermore, Cell Counting Kit-8 (CCK-8) assay, Transwell migration, Transwell invasion, and flow cytometry assays were conducted to evaluate the role of NPM1 in the proliferation, migration, invasion, and apoptosis in LUAD cell lines. Moreover, glycolysis-related indicators were determined using corresponding kits. Additionally, the mechanism of NPM1 involvement was further evaluated through NPM1 silencing experiments.
Results: NPM1 was upregulated in two human LUAD cell lines (p < 0.001). Glycolysis was enhanced in LUAD cell lines (p < 0.05). After inhibiting the expression of NPM1, the proliferation, migration, and invasion were significantly reduced in LUAD cell lines but the apoptosis was increased (p < 0.05). Furthermore, a substantial reduction in glycolytic flux and an elevation in mitochondrial respiration were observed (p < 0.05).
Conclusion: These findings reveal that NPM1 promotes LUAD progression by mediating glycolysis, offering a novel therapeutic target for treating LUAD.
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Background: Organophosphate poisoning poses a significant health burden due to the absence of specific pharmacological antidotes. To address this issue, we explored the potential of nanoparticles for organophosphate detoxification, focusing on biomimetic nanoparticles with natural cell membrane coatings.
Methods: We developed membrane-cloaked oil nano-sponges by combining red blood cell (RBC) membranes and oil to create a dual-model detoxification system for organophosphates. The oil component non-specifically absorbed organophosphate poisons, while the membrane-bound acetylcholinesterase enzyme is specifically bound to the toxic molecules, preserving intrinsic acetylcholinesterase function. We evaluated the detoxification capacity of this system using chlorpyrifos as a model insecticide in a rabbit model.
Results: The prepared oil nano-sponge exhibited potent antidote capabilities against organophosphate poisoning and demonstrated efficacy in poisoning prevention. The safety evaluation revealed no adverse effects on the gross appearance or histopathological sections of the liver, kidneys, spleen, lungs, and heart.
Conclusions: In summary, our novel membrane-cloaked oil nano-sponge proved to be a safe and effective antidote for organophosphate poisoning in rabbits. These findings have the potential for extrapolation to other species, offering a promising solution to mitigate inadvertent organophosphate poisoning.
