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European Journal of Medical Research Jun 2024Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive... (Review)
Review
Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive proliferation, uncontrolled growth, invasion of nearby tissues, and spread to distant organs. Its progression involves a complex interplay of several elements and processes. Extracellular vesicles (EVs) serve as critical intermediaries in intercellular communication, transporting critical molecules such as lipids, RNA, membrane, and cytoplasmic proteins between cells. They significantly contribute to the progression, development, and dissemination of primary tumors by facilitating the exchange of information and transmitting signals that regulate tumor growth and metastasis. However, EVs do not have a singular impact on cancer; instead, they play a multifaceted dual role. Under specific circumstances, they can impede tumor growth and influence cancer by delivering oncogenic factors or triggering an immune response. Furthermore, EVs from different sources demonstrate distinct advantages in inhibiting cancer. This research examines the biological characteristics of EVs and their involvement in cancer development to establish a theoretical foundation for better understanding the connection between EVs and cancer. Here, we discuss the potential of EVs from various sources in cancer therapy, as well as the current status and future prospects of engineered EVs in developing more effective cancer treatments.
Topics: Extracellular Vesicles; Humans; Neoplasms; Cell Communication; Animals
PubMed: 38943222
DOI: 10.1186/s40001-024-01937-x -
BMC Pharmacology & Toxicology Jun 2024Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were...
Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, β-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC of 8.4 and 17.9 μM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.
Topics: Humans; Colorectal Neoplasms; Chalcones; Antineoplastic Agents; fas Receptor; Structure-Activity Relationship; HCT116 Cells; Molecular Docking Simulation; Cell Movement; Cell Cycle; Cell Line, Tumor
PubMed: 38943212
DOI: 10.1186/s40360-024-00758-2 -
Journal of Extracellular Vesicles Jul 2024Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment.... (Review)
Review
Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane-bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.
Topics: Humans; Extracellular Vesicles; Osteoarthritis; Biomarkers; Animals
PubMed: 38943211
DOI: 10.1002/jev2.12435 -
Lipids in Health and Disease Jun 2024Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor... (Review)
Review
Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.
Topics: Humans; Lysophospholipids; Bone Neoplasms; Signal Transduction; Receptors, Lysophosphatidic Acid; Animals
PubMed: 38943207
DOI: 10.1186/s12944-024-02196-9 -
Microbiome Jun 2024Population stratification based on interindividual variability in gut microbiota composition has revealed the existence of several ecotypes named enterotypes in humans...
BACKGROUND
Population stratification based on interindividual variability in gut microbiota composition has revealed the existence of several ecotypes named enterotypes in humans and various animal species. Enterotypes are often associated with environmental factors including diet, but knowledge of the role of host genetics remains scarce. Moreover, enterotypes harbor functionalities likely associated with varying abilities and susceptibilities of their host. Previously, we showed that under controlled conditions, 60-day-old pig populations consistently split into two enterotypes with either Prevotella and Mitsuokella (PM enterotype) or Ruminococcus and Treponema (RT enterotype) as keystone taxa. Here, our aim was to rely on pig as a model to study the influence of host genetics to assemble enterotypes, and to provide clues on enterotype functional differences and their links with growth traits.
RESULTS
We established two pig lines contrasted for abundances of the genera pairs specifying each enterotype at 60 days of age and assessed them for fecal microbiota composition and growth throughout three consecutive generations. Response to selection across three generations revealed, per line, an increase in the prevalence of the selected enterotype and in the average relative abundances of directly and indirectly selected bacterial genera. The PM enterotype was found less diverse than the RT enterotype but more efficient for piglet growth during the post-weaning period. Shotgun metagenomics revealed differentially abundant bacterial species between the two enterotypes. By using the KEGG Orthology database, we show that functions related to starch degradation and polysaccharide metabolism are enriched in the PM enterotype, whereas functions related to general nucleoside transport and peptide/nickel transport are enriched in the RT enterotype. Our results also suggest that the PM and RT enterotypes might differ in the metabolism of valine, leucin, and isoleucine, favoring their biosynthesis and degradation, respectively.
CONCLUSION
We experimentally demonstrated that enterotypes are functional ecosystems that can be selected as a whole by exerting pressure on the host genetics. We also highlight that holobionts should be considered as units of selection in breeding programs. These results pave the way for a holistic use of host genetics, microbiota diversity, and enterotype functionalities to understand holobiont shaping and adaptation. Video Abstract.
Topics: Animals; Gastrointestinal Microbiome; Swine; Feces; Bacteria; Metagenomics; Prevotella; Ruminococcus; Treponema
PubMed: 38943206
DOI: 10.1186/s40168-024-01827-8 -
Cancer Cell International Jun 2024Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance....
BACKGROUND
Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.
METHODS
Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.
RESULTS
PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.
CONCLUSION
Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.
PubMed: 38943199
DOI: 10.1186/s12935-024-03416-z -
Alzheimer's Research & Therapy Jun 2024Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs).... (Comparative Study)
Comparative Study
BACKGROUND
Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs.
METHODS
Single-molecule enzyme-linked assays were used to quantify Aβ42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples.
RESULTS
The soluble plasma Aβ42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aβ40, Aβ42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions.
CONCLUSION
Soluble plasma Aβ42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aβ release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aβ and tau need correction by NDEVs for better AD risk identification in CN populations.
Topics: Humans; Alzheimer Disease; Extracellular Vesicles; Biomarkers; Female; Male; Amyloid beta-Peptides; Aged; tau Proteins; Peptide Fragments; Aged, 80 and over; Middle Aged; Cohort Studies; Apolipoprotein E4
PubMed: 38943196
DOI: 10.1186/s13195-024-01508-6 -
Cell Communication and Signaling : CCS Jun 2024The neonatal mammalian heart exhibits considerable regenerative potential following injury through cardiomyocyte proliferation, whereas mature cardiomyocytes withdraw...
BACKGROUND
The neonatal mammalian heart exhibits considerable regenerative potential following injury through cardiomyocyte proliferation, whereas mature cardiomyocytes withdraw from the cell cycle and lose regenerative capacities. Therefore, investigating the mechanisms underlying neonatal cardiomyocyte proliferation and regeneration is crucial for unlocking the regenerative potential of adult mammalian heart to repair damage and restore contractile function following myocardial injury.
METHODS
The Tudor staphylococcal nuclease (Tudor-SN) transgenic (TG) or cardiomyocyte-specific knockout mice (Myh6-Tudor-SN ) were generated to investigate the role of Tudor-SN in cardiomyocyte proliferation and heart regeneration following apical resection (AR) surgery. Primary cardiomyocytes isolated from neonatal mice were used to assess the influence of Tudor-SN on cardiomyocyte proliferation in vitro. Affinity purification and mass spectrometry were employed to elucidate the underlying mechanism. H9c2 cells and mouse myocardia with either overexpression or knockout of Tudor-SN were utilized to assess its impact on the phosphorylation of Yes-associated protein (YAP), both in vitro and in vivo.
RESULTS
We previously identified Tudor-SN as a cell cycle regulator that is highly expressed in neonatal mice myocardia but downregulated in adults. Our present study demonstrates that sustained expression of Tudor-SN promotes and prolongs the proliferation of neonatal cardiomyocytes, improves cardiac function, and enhances the ability to repair the left ventricular apex resection in neonatal mice. Consistently, cardiomyocyte-specific knockout of Tudor-SN impairs cardiac function and retards recovery after injury. Tudor-SN associates with YAP, which plays important roles in heart development and regeneration, inhibiting phosphorylation at Ser 127 and Ser 397 residues by preventing the association between Large Tumor Suppressor 1 (LATS1) and YAP, correspondingly maintaining stability and promoting nuclear translocation of YAP to enhance the proliferation-related genes transcription.
CONCLUSION
Tudor-SN regulates the phosphorylation of YAP, consequently enhancing and prolonging neonatal cardiomyocyte proliferation under physiological conditions and promoting neonatal heart regeneration after injury.
Topics: Animals; Myocytes, Cardiac; Regeneration; Phosphorylation; Cell Proliferation; YAP-Signaling Proteins; Animals, Newborn; Adaptor Proteins, Signal Transducing; Mice; Cell Cycle Proteins; Heart; Mice, Knockout; Rats
PubMed: 38943195
DOI: 10.1186/s12964-024-01715-6 -
Molecular Brain Jun 2024The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar...
The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar inflammation induces social avoidance in mice. Oxytocin regulates social relationship and expression pattern of the oxytocin receptor in the brain is related to social behaviors. However, the expression patterns of the oxytocin receptor in the cerebellum remain controversial. Here, we report that the expression patterns of the oxytocin receptor in the cerebellum are highly variable among knock-in transgenic lines. We used Oxtr-Cre knock-in mice combined with a fluorescent reporter line and found that oxytocin receptor expression in Bergmann glia was more variable than that in Purkinje cells. We found that physical damage with inflammation induced the selective upregulation of the oxytocin receptor in Bergmann glia. Our findings indicate high variability in oxytocin receptor expression in the cerebellum and suggest that the oxytocin receptor can affect neural processing in pathological conditions, such as inflammation.
Topics: Receptors, Oxytocin; Animals; Neuroglia; Up-Regulation; Cerebellum; Inflammation; Mice, Transgenic; Mice, Inbred C57BL; Mice; Male; Purkinje Cells
PubMed: 38943193
DOI: 10.1186/s13041-024-01114-5 -
Veterinary Research Jun 2024Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal...
Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal model for waterfowl among migratory birds, studying and dissecting the antiviral immunity and viral evasion in duck cells may pave a path to deciphering these puzzles. Here, we studied the mechanism of antiviral autophagy mediated by duck STING in DEF cells. The results collaborated that duck STING could significantly enhance LC3B-II/I turnover, LC3B-EGFP puncta formation, and mCherry/EGFP ratio, indicating that duck STING could induce autophagy. The autophagy induced by duck STING is not affected by shRNA knockdown of ATG5 expression, deletion of the C-terminal tail of STING, or TBK1 inhibitor BX795 treatment, indicating that duck STING activated non-classical selective autophagy is independent of interaction with TBK1, TBK1 phosphorylation, and interferon (IFN) signaling. The STING R235A mutant and Sar1A/B kinase mutant abolished duck STING induced autophagy, suggesting binding with cGAMP and COPII complex mediated transport are the critical prerequisite. Duck STING interacted with LC3B through LIR motifs to induce autophagy, the LIR 4/7 motif mutants of duck STING abolished the interaction with LC3B, and neither activated autophagy nor IFN expression, indicating that duck STING associates with LC3B directed autophagy and dictated innate immunity activation. Finally, we found that duck STING mediated autophagy significantly inhibited duck plague virus (DPV) infection via ubiquitously degraded viral proteins. Our study may shed light on one scenario about the control and evasion of diseases transmitted by migratory birds.
Topics: Animals; Ducks; Autophagy; Signal Transduction; Mardivirus; Interferons; Alphaherpesvirinae; Immunity, Innate; Membrane Proteins; Poxviridae Infections
PubMed: 38943190
DOI: 10.1186/s13567-024-01338-2