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Microorganisms May 2024Fungi are ubiquitous and metabolically versatile. Their dispersion has important scientific, environmental, health, and economic implications. They can be dispersed...
Fungi are ubiquitous and metabolically versatile. Their dispersion has important scientific, environmental, health, and economic implications. They can be dispersed through the air by the aerosolization of near surfaces or transported from distant sources. Here, we tested the contribution of local (scale of meters) versus regional (kilometers) sources by analyzing an airborne fungal community by ITS sequencing around a copper mine in the North of Chile. The mine was the regional source, whereas the soil and vegetal detritus were the local sources at each point. The airborne community was highly homogeneous at ca. 2000 km, impeding the detection of regional or local contributions. Ascomycota was the dominant phylum in the three communities. Soil and vegetal detritus communities had lower alpha diversity, but some taxa had abundance patterns related to the distance from the mine and altitude. On the contrary, the air was compositionally even and unrelated to environmental or spatial factors, except for altitude. The presence of plant pathogens in the air suggests that other distant sources contribute to this region's airborne fungal community and reinforces the complexity of tracking the sources of air microbial communities in a real world where several natural and human activities coexist.
PubMed: 38792765
DOI: 10.3390/microorganisms12050934 -
Journal of Clinical Medicine May 2024The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic...
The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed ( < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation.
PubMed: 38792509
DOI: 10.3390/jcm13102968 -
Genes Apr 2024P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function...
P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function as a tumor suppressor, elevated p53 levels can paradoxically contribute to tumorigenesis, influenced by factors such as exposure to carcinogens, genetic mutations, and viral infections. This phenomenon is observed across a spectrum of cancer types, including bladder (BLCA), ovarian (OV), cervical (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). This broad spectrum of cancers is often associated with increased aggressiveness and recurrence risk. Effective therapeutic strategies targeting tumors with p53 overexpression require a comprehensive approach, integrating targeted interventions aimed at the p53 gene with conventional modalities such as chemotherapy, radiation therapy, and targeted drugs. In this extensive study, we present a detailed analysis shedding light on the multifaceted role of TP53 across various cancers, with a specific emphasis on its impact on disease-free survival (DFS). Leveraging data from the TCGA database and the GTEx dataset, along with GEPIA, UALCAN, and STRING, we identify TP53 overexpression as a significant prognostic indicator, notably pronounced in prostate adenocarcinoma (PRAD). Supported by compelling statistical significance ( < 0.05), our analysis reveals the distinct influence of TP53 overexpression on DFS outcomes in PRAD. Additionally, graphical representations of overall survival (OS) underscore the notable disparity in OS duration between tumors exhibiting elevated TP53 expression (depicted by the red line) and those with lower TP53 levels (indicated by the blue line). The hazard ratio (HR) further emphasizes the profound impact of TP53 on overall survival. Moreover, our investigation delves into the intricate TP53 protein network, unveiling genes exhibiting robust positive correlations with TP53 expression across 13 out of 27 cancers. Remarkably, negative correlations emerge with pivotal tumor suppressor genes. This network analysis elucidates critical proteins, including SIRT1, CBP, p300, ATM, DAXX, HSP 90-alpha, Mdm2, RPA70, 14-3-3 protein sigma, p53, and ASPP2, pivotal in regulating cell cycle dynamics, DNA damage response, and transcriptional regulation. Our study underscores the paramount importance of deciphering TP53 dynamics in cancer, providing invaluable insights into tumor behavior, disease-free survival, and potential therapeutic avenues.
Topics: Humans; Tumor Suppressor Protein p53; Neoplasms; Computational Biology; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor
PubMed: 38790205
DOI: 10.3390/genes15050577 -
European Journal of Pharmaceutical... Aug 2024Myocardial fibrosis can induce cardiac dysfunction and remodeling. Great attention has been paid to traditional chinese medicine (TCM) 's effectiveness in treating MF....
Elucidating the mechanism of action of Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract on radiation-induced myocardial fibrosis based on network pharmacology and experimental research.
Myocardial fibrosis can induce cardiac dysfunction and remodeling. Great attention has been paid to traditional chinese medicine (TCM) 's effectiveness in treating MF. Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract (RAS-RA), which is a key TCM compound preparation, have high efficacy in regulating inflammation. However, studies on its therapeutic effect on radiation-induced myocardial fibrosis (RIMF) are rare. In this study, RAS-RA had therapeutic efficacy in RIMF and elucidated its mechanism of action. First, we formulated the prediction network that described the relation of RAS-RA with RIMF according to data obtained in different databases. Then, we conducted functional enrichment to investigate the functions and pathways associated with potential RIMF targets for RAS-RA. In vivo experiments were also performed to verify these functions and pathways. Second, small animal ultrasound examinations, H&E staining, Masson staining, transmission electron microscopy, Enzyme-linked immunosorbent assay (ELISA), Western-blotting, Immunohistochemical method and biochemical assays were conducted to investigate the possible key anti-RIMF pathway in RAS-RA. In total, 440 targets were detected in those 21 effective components of RAS-RA; meanwhile, 1,646 RIMF-related disease targets were also discovered. After that, PPI network analysis was conducted to identify 20 key targets based on 215 overlap gene targets. As indicated by the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis results, inflammation and PI3K/AKT/mTOR pathways might have important effects on the therapeutic effects on RIMF. Molecular docking analysis revealed high binding of effective components to targets (affinity < -6 kcal/mol). Based on experimental verification results, RAS-RA greatly mitigated myocardial fibrosis while recovering the cardiac activity of rats caused by X-rays. According to relevant protein expression profiles, the PI3K/AKT/mTOR pathway was important for anti-fibrosis effect of RAS-RA. Experimental studies showed that RAS-RA improved cardiac function, decreased pathological damage and collagen fiber deposition in cardiac tissues, and improved the mitochondrial structure of the heart of rats. RAS-RA also downregulated TNF-α, IL-6, and IL-1β levels. Additionally, RAS-RA improved the liver and kidney functions and pathological injury of rat kidney and liver tissues, enhanced liver and kidney functions, and protected the liver and kidneys. RAS-RA also increased PI3K, AKT and mTOR protein levels within cardiac tissues and downregulated α-SMA, Collagen I, and Collagen III. The findings of this study suggested that RAS-RA decreased RIMF by suppressing collagen deposition and inflammatory response by inhibiting the PI3K/AKT/mTOR pathway. Thus, RAS-RA was the potential therapeutic agent used to alleviate RIMF.
Topics: Animals; Angelica sinensis; Drugs, Chinese Herbal; Male; Fibrosis; Network Pharmacology; Rats, Sprague-Dawley; Rats; Astragalus Plant; Myocardium; Ultrafiltration; Signal Transduction; Cardiomyopathies; TOR Serine-Threonine Kinases
PubMed: 38788908
DOI: 10.1016/j.ejps.2024.106794 -
Journal of Functional Biomaterials Apr 2024Cargo encapsulation through emulsion-based methods has been pondered over the years. Although several microemulsification techniques have been employed for the...
Cargo encapsulation through emulsion-based methods has been pondered over the years. Although several microemulsification techniques have been employed for the microcapsule's synthesis, there are still no clear guidelines regarding the suitability of one technique over the others or the impacts on the morphological and physicochemical stability of the final particles. Therefore, in this systematic study, we investigated the influence of synthesis parameters on the fabrication of emulsion-based microcapsules concerning morphological and physicochemical properties. Using poly(urea-formaldehyde) (PUF) microcapsules as a model system, and after determining the optimal core/shell ratio, we tested three different microemulsification techniques (magnetic stirring, ultrasonication, and mechanical stirring) and two different cargo types (100% TEGDMA (Triethylene glycol dimethacrylate) and 80% TEGDMA + 20% DMAM (N,N-Dimethylacrylamide)). The resulting microcapsules were characterized via optical and scanning electron microscopies, followed by size distribution analysis. The encapsulation efficiency was obtained through the extraction method, and the percentage reaction yield was calculated. Physicochemical properties were assessed by incubating the microcapsules under different osmotic pressures for 1 day and 1, 2, or 4 weeks. The data were analyzed statistically with one-way ANOVA and Tukey's tests (α = 0.05). Overall, the mechanical stirring resulted in the most homogeneous and stable microcapsules, with an increased reaction yield from 100% to 50% in comparison with ultrasonication and magnetic methods, respectively. The average microcapsule diameter ranged from 5 to 450 µm, with the smallest ones in the ultrasonication and the largest ones in the magnetic stirring groups. The water affinities of the encapsulated cargo influenced the microcapsule formation and stability, with the incorporation of DMAM leading to more homogeneous and stable microcapsules. Environmental osmotic pressure led to cargo loss or the selective swelling of the shells. In summary, this systematic investigation provides insights and highlights commonly overlooked factors that can influence microcapsule fabrication and guide the choice based on a diligent analysis of therapeutic niche requirements.
PubMed: 38786629
DOI: 10.3390/jfb15050117 -
Gels (Basel, Switzerland) May 2024Sacran is a supergiant cyanobacterial polysaccharide that forms mesogenic supercoil rods that exhibit liquid crystalline (LC) gels at deficient concentrations of around...
Structural Analyses of Polysaccharides Extracted from Cyanobacterial Extracellular Gels and Oriented Liquid Crystalline Microfiber Processing by Poly(vinyl alcohol)-Assisted Electrospinning.
Sacran is a supergiant cyanobacterial polysaccharide that forms mesogenic supercoil rods that exhibit liquid crystalline (LC) gels at deficient concentrations of around 0.5 wt%, and has several bioactive stimuli-responsive functions. Here, we attempted to form oriented microfibers of sacran by electrospinning, following structural analyses of the sacran rods. A heterogeneous acid-hydrolysis method using a protonated cation-exchange resin was adopted to examine the short-time exposition of concentrated acid to sacran rods. From the supernatant, the oligomeric fraction that was soluble in water and methanol was isolated. The oligomeric fraction had a main sugar ratio of -Glc:-Glc:-Xyl:-Xyl:-Rha of 2:5:1.5:1.5:4 (Glc:Xyl:Rha = 7 (=4 + 3):3:4), and it was speculated that the sacran structure includes rhamnoglucan and xyloglucan (4:3), which are generally rigid enough to exhibit LC. To make oriented microfibers of LC sacran, solubility testing was performed on sacran to find good new solvents of polyhydroxy alcohols such as ethylene glycol, 1,2-propanediol, and glycerol. The oriented film was prepared from a sacran aqueous solution where calcium compound particles deposited on the film are different from polyhydroxy alcohol solutions. Although sacran could not form microfibers by itself, polymer composite microfibers of sacran with poly(vinyl alcohol) were prepared by electrospinning. Cross-polarizing microscopy revealed the molecular orientation of the microfibers.
PubMed: 38786237
DOI: 10.3390/gels10050321 -
Biology Apr 2024Adipose tissue plays an important role in regulating body temperature and metabolism, with white adipocytes serving as storage units for energy. Recent research focused...
Adipose tissue plays an important role in regulating body temperature and metabolism, with white adipocytes serving as storage units for energy. Recent research focused on the browning of white adipocytes (beige adipocytes), causing thermogenesis and lipolysis. The process of browning is linked to the activation of uncoupling protein (UCP) expression, which can be mediated by the β3 adrenergic receptor pathway. Transcriptional factors, such as peroxisome proliferator activated receptor γ () and PPARγ coactivator 1 alpha, play vital roles in cell fate determination for fat cells. Beige adipocytes have metabolic therapeutic potential to combat diseases such as obesity, diabetes mellitus, and dyslipidemia, owing to their significant impact on metabolic functions. However, the molecular mechanisms that cause the induction of browning are unclear. Therefore, research using animal models and primary culture is essential to provide an understanding of browning for further application in human metabolic studies. Pigs have physiological similarities to humans; hence, they are valuable models for research on adipose tissue. This study demonstrates the browning potential of pig white adipocytes through primary culture experiments. The results show that upregulation of gene expression and fragmentation of lipid droplets into smaller particles occur due to isoproterenol stimulation, which activates beta-adrenergic receptor signaling. Furthermore, and were found to activate the UCP3 promoter region, similar to that of UCP1. These findings suggest that pigs undergo metabolic changes that induce browning in white adipocytes, providing a promising approach for metabolic research with potential implications for human health. This study offers valuable insights into the mechanism of adipocyte browning using pig primary culture that can enhance our understanding of human metabolism, leading to cures for commonly occurring diseases.
PubMed: 38785767
DOI: 10.3390/biology13050284 -
Cell Jun 2024Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi,...
Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.
Topics: Animals; Mice; Intestinal Mucosa; Extracellular Matrix; Myosin Type II; Mesoderm; Mesenchymal Stem Cells; Receptor, Platelet-Derived Growth Factor alpha; Morphogenesis; Matrix Metalloproteinases
PubMed: 38781967
DOI: 10.1016/j.cell.2024.04.039 -
The Journal of Clinical Investigation May 2024PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal...
PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.
PubMed: 38781024
DOI: 10.1172/JCI175949 -
Advances in Radiation Oncology Apr 2024Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/β, STS may be more responsive...
PURPOSE
Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/β, STS may be more responsive to hypofractionated radiation therapy (RT), which is often limited by long-term toxicity risk to surrounding normal tissue. An isotoxic approach using a hypofractionated accelerated radiation dose-painting (HARD) regimen allows for dosing based on clinical risk while sparing adjacent organs at risk.
METHODS AND MATERIALS
We retrospectively identified patients from 2019 to 2022 with unresected STS who received HARD with dose-painting to high, intermediate, and low-risk regions of 3.0 Gy, 2.5 Gy, and 2.0 to 2.3 Gy, respectively, in 20 to 22 fractions. Clinical endpoints included local control, locoregional control, progression free survival, overall survival, and toxicity outcomes.
RESULTS
Twenty-seven consecutive patients were identified and had a median age of 68 years and tumor size of 7.0 cm (range, 1.2-21.0 cm). Tumors were most often high-grade (70%), stage IV (70%), located in the extremities (59%), and locally recurrent (52%). With a median follow-up of 33.4 months, there was a 3-year locoregional control rate of 100%. The 3-year overall and progression-free survival were 44.9% and 23.3%, respectively. There were 5 (19%) acute and 2 (7%) late grade 3 toxicities, and there were no grade 4 or 5 toxicities at any point.
CONCLUSIONS
The HARD regimen is a safe method of dose-escalating STS, with durable 3-year locoregional control. This approach is a promising alternative for unresected STS, though further follow-up is required to determine long-term control and toxicity.
PubMed: 38778821
DOI: 10.1016/j.adro.2024.101447