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Cells Jun 2024Authors have demonstrated that apoptosis activation is a pathway related to cartilage degradation characteristics of the OA process. Autophagy is an adaptive response to...
Authors have demonstrated that apoptosis activation is a pathway related to cartilage degradation characteristics of the OA process. Autophagy is an adaptive response to protect cells from various environmental changes, and defects in autophagy are linked to cell death. In this sense, decreased autophagy of chondrocytes has been observed in OA articular cartilage. The aim of this work was to study the role of OA mitochondria in apoptosis, autophagy, and senescence, using OA and Normal (N) transmitochondrial cybrids. Results: OA cybrids incubated with menadione showed a higher percentage of late apoptosis and necrosis than N cybrids. Stimulation of cybrids with staurosporine and IL-1β showed that OA cybrids were more susceptible to undergoing apoptosis than N cybrids. An analysis of the antioxidant response using menadione on gene expression revealed a lower expression of nuclear factor erythroid 2-like 2 and superoxide dismutase 2 in OA than N cybrids. Activation of microtubule-associated protein 1A/1B-light chain 3 was reduced in OA compared to N cybrids. However, the percentage of senescent cells was higher in OA than N cybrids. Conclusion: This work suggests that mitochondria from OA patients could be involved in the apoptosis, autophagy, and senescence of chondrocytes described in OA cartilage.
Topics: Autophagy; Humans; Osteoarthritis; Apoptosis; Cellular Senescence; Mitochondria; Chondrocytes; Microtubule-Associated Proteins; NF-E2-Related Factor 2; Superoxide Dismutase; Aged; Interleukin-1beta; Male; Middle Aged; Vitamin K 3; Female
PubMed: 38891108
DOI: 10.3390/cells13110976 -
Journal of Nanobiotechnology Jun 2024Functional drug testing (FDT) with patient-derived tumor cells in microfluidic devices is gaining popularity. However, the majority of previously reported microfluidic...
BACKGROUND
Functional drug testing (FDT) with patient-derived tumor cells in microfluidic devices is gaining popularity. However, the majority of previously reported microfluidic devices for FDT were limited by at least one of these factors: lengthy fabrication procedures, absence of tumor progenitor cells, lack of clinical correlation, and mono-drug therapy testing. Furthermore, personalized microfluidic models based on spheroids derived from oral cancer patients remain to be thoroughly validated. Overcoming the limitations, we develop 3D printed mold-based, dynamic, and personalized oral stem-like spheroids-on-a-chip, featuring unique serpentine loops and flat-bottom microwells arrangement.
RESULTS
This unique arrangement enables the screening of seven combinations of three drugs on chemoresistive cancer stem-like cells. Oral cancer patients-derived stem-like spheroids (CD 44) remains highly viable (> 90%) for 5 days. Treatment with a well-known oral cancer chemotherapy regimen (paclitaxel, 5 fluorouracil, and cisplatin) at clinically relevant dosages results in heterogeneous drug responses in spheroids. These spheroids are derived from three oral cancer patients, each diagnosed with either well-differentiated or moderately-differentiated squamous cell carcinoma. Oral spheroids exhibit dissimilar morphology, size, and oral tumor-relevant oxygen levels (< 5% O). These features correlate with the drug responses and clinical diagnosis from each patient's histopathological report.
CONCLUSIONS
Overall, we demonstrate the influence of tumor differentiation status on treatment responses, which has been rarely carried out in the previous reports. To the best of our knowledge, this is the first report demonstrating extensive work on development of microfluidic based oral cancer spheroid model for personalized combinatorial drug screening. Furthermore, the obtained clinical correlation of drug screening data represents a significant advancement over previously reported personalized spheroid-based microfluidic devices. Finally, the maintenance of patient-derived spheroids with high viability under oral cancer relevant oxygen levels of less than 5% O is a more realistic representation of solid tumor microenvironment in our developed device.
Topics: Humans; Mouth Neoplasms; Spheroids, Cellular; Lab-On-A-Chip Devices; Neoplastic Stem Cells; Drug Screening Assays, Antitumor; Antineoplastic Agents; Precision Medicine; Printing, Three-Dimensional; Fluorouracil; Paclitaxel
PubMed: 38890730
DOI: 10.1186/s12951-024-02625-y -
Radiation Oncology (London, England) Jun 2024This retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant...
OBJECTIVE
This retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant chemoradiotherapy (CRT).
METHODS
Retrospective analysis of EC patients who underwent adjuvant CRT from January 2012 to June 2023 in the Department of Gynecology and Oncology of the First Affiliated Hospital of Shandong First Medical University. Neutropenia was defined as an Absolute Neutrophil Count (ANC) of peripheral blood neutrophils below 2 × 10/L. Factors affecting neutropenia in EC patients treated with CRT using Generalized Estimating Equation (GEE), and Logistic regression was used to further analyze the effect of adding radiotherapy to different chemotherapy cycles on neutropenia, so that patients receive optimal adjuvant CRT while the risk of neutropenia is appropriately controlled.
RESULTS
A total of 144 patients met the inclusion criteria. They underwent 330 cycles of adjuvant chemotherapy, of whom 96 (66.7%) developed neutropenia, which occurred 140 times. The results of one-way GEE analysis showed that before CRT, White Blood Cell (WBC) (OR = 0.827; 95%CI, 0.701-0.976), ANC (OR = 0.749; 95%CI, 0.586-0.957), Absolute Monocyte Count (AMC) (OR = 0.047; 95%CI, 0.008-0.283), Blood Urea Nitrogen (BUN) (OR = 0.857; 95%CI, 0.741-0.991), platinum and docetaxel (platinum/docetaxel) dosing regimen (OR = 2.284; 95%CI, 1.130-4.618) were associated with neutropenia with adjuvant CRT for EC (p < 0.05), results of multifactorial GEE analysis showed that before adjuvant CRT ANC (OR = 0.552; 95%CI, 0.973-2.231), AMC (OR = 0.047; 95%CI, 0.004-0.052), platinum/docetaxel (OR = 2.437; 95%CI, 1.087-5.464) were an independent influence on neutropenia in adjuvant CRT for EC (p < 0.05). Multifactorial Logistic regression shows addition of radiotherapy to the first cycle of chemotherapy (OR = 4.413; 95%CI, 1.238-18.891) was an independent influence of neutropenia (p < 0.05).
CONCLUSIONS
Patients with low pre-CRT ANC and AMC, platinum/docetaxel dosing regimens need to be closely monitored during each cycle of CRT. Also, the concurrent addition of radiotherapy should be avoided during the first cycle of chemotherapy.
Topics: Humans; Female; Retrospective Studies; Endometrial Neoplasms; Neutropenia; Middle Aged; Aged; Chemoradiotherapy, Adjuvant; Adult; Antineoplastic Combined Chemotherapy Protocols; Prognosis; Docetaxel; Risk Factors
PubMed: 38890652
DOI: 10.1186/s13014-024-02469-8 -
BMC Plant Biology Jun 2024The quality of maize kernels is significantly enhanced by amino acids, which are the fundamental building blocks of proteins. Meanwhile, calcium (Ca) and magnesium (Mg),...
BACKGROUND
The quality of maize kernels is significantly enhanced by amino acids, which are the fundamental building blocks of proteins. Meanwhile, calcium (Ca) and magnesium (Mg), as important nutrients for maize growth, are vital in regulating the metabolic pathways and enzyme activities of amino acid synthesis. Therefore, our study analyzed the response process and changes of amino acid content, endogenous hormone content, and antioxidant enzyme activity in kernels to the coupling addition of sugar alcohol-chelated Ca and Mg fertilizers with spraying on maize.
RESULT
(1) The coupled addition of Ca and Mg fertilizers increased the Ca and Mg content, endogenous hormone components (indole-3-acetic acid, IAA; gibberellin, GA; zeatin riboside, ZR) content, antioxidant enzyme activity, and amino acid content of maize kernels. The content of Ca and Mg in kernels increased with the increasing levels of Ca and Mg fertilizers within a certain range from the filling to the wax ripening stage, and significantly positively correlated with antioxidant enzyme activities. (2) The contents of IAA, GA, and ZR continued to rise, and the activities of superoxide dismutase (SOD) and catalase (CAT) were elevated, which effectively enhanced the ability of cells to resist oxidative damage, promoted cell elongation and division, and facilitated the growth and development of maize. However, the malondialdehyde (MDA) content increased consistently, which would attack the defense system of the cell membrane plasma to some extent. (3) Leucine (LEU) exhibited the highest percentage of essential amino acid components and a gradual decline from the filling to the wax ripening stage, with the most substantial beneficial effect on essential amino acids. (4) CAT and SOD favorably governed essential amino acids, while IAA and MDA negatively regulated them. The dominant physiological driving pathway for the synthesis of essential amino acids was "IAA-CAT-LEU", in which IAA first negatively drove CAT activity, and CAT then advantageously controlled LEU synthesis.
CONCLUSION
These findings provide a potential approach to the physiological and biochemical metabolism of amino acid synthesis, and the nutritional quality enhancement of maize kernel.
Topics: Zea mays; Magnesium; Amino Acids; Calcium; Plant Growth Regulators; Fertilizers; Indoleacetic Acids; Antioxidants; Superoxide Dismutase; Gibberellins
PubMed: 38890571
DOI: 10.1186/s12870-024-05287-y -
BMC Genomics Jun 2024Cyathus olla, belonging to the genus Cyathus within the order Agaricales, is renowned for its bird's nest-like fruiting bodies and has been utilized in folk medicine....
Cyathus olla, belonging to the genus Cyathus within the order Agaricales, is renowned for its bird's nest-like fruiting bodies and has been utilized in folk medicine. However, its genome remains poorly understood. To investigate genomic diversity within the genus Cyathus and elucidate biosynthetic pathways for medicinal compounds, we generated a high-quality genome assembly of C. olla with fourteen chromosomes. The comparative genome analysis revealed variations in both genomes and specific functional genes within the genus Cyathus. Phylogenomic and gene family variation analyses provided insights into evolutionary divergence, as well as genome expansion and contraction in individual Cyathus species and 36 typical Basidiomycota. Furthermore, analysis of LTR-RT and Ka/Ks revealed apparent whole-genome duplication (WGD) events its genome. Through genome mining and metabolite profiling, we identified the biosynthetic gene cluster (BGC) for cyathane diterpenes from C. olla. Furthermore, we predicted 32 BGCs, containing 41 core genes, involved in other bioactive metabolites. These findings represent a valuable genomic resource that will enhance our understanding of Cyathus species genetic diversity. The genome analysis of C. olla provides insights into the biosynthesis of medicinal compounds and establishes a fundamental basis for future investigations into the genetic basis of chemodiversity in this significant medicinal fungus.
Topics: Genome, Fungal; Phylogeny; Multigene Family; Biosynthetic Pathways; Agaricales; Diterpenes; Genomics; Metabolome
PubMed: 38890562
DOI: 10.1186/s12864-024-10528-3 -
Scientific Reports Jun 2024Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents...
Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m)-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14-0.86, P = 0.02 for all cycles; 0.26, 0.11-0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.
Topics: Humans; Docetaxel; Dexamethasone; Female; Breast Neoplasms; Hand-Foot Syndrome; Middle Aged; Retrospective Studies; Aged; Adult; Dose-Response Relationship, Drug; Antineoplastic Agents
PubMed: 38890326
DOI: 10.1038/s41598-024-64553-z -
Nature Communications Jun 2024Faecal microbiota plays a critical role in human health, but its relationship with nutritional status among schoolchildren remains under-explored. Here, in a... (Randomized Controlled Trial)
Randomized Controlled Trial
Faecal microbiota of schoolchildren is associated with nutritional status and markers of inflammation: a double-blinded cluster-randomized controlled trial using multi-micronutrient fortified rice.
Faecal microbiota plays a critical role in human health, but its relationship with nutritional status among schoolchildren remains under-explored. Here, in a double-blinded cluster-randomized controlled trial on 380 Cambodian schoolchildren, we characterize the impact of six months consumption of two types of rice fortified with different levels of vitamins and minerals on pre-specified outcomes. We investigate the association between the faecal microbiota (16SrRNA sequencing) and age, sex, nutritional status (underweight, stunting), micronutrient status (iron, zinc and vitamin A deficiencies, anaemia, iron deficient anaemia, hemoglobinopathy), inflammation (systemic, gut), and parasitic infection. We show that the faecal microbiota is characterised by a surprisingly high proportion of Lactobacillaceae. We discover that deficiencies in specific micronutrients, such as iron and vitamin A, correlate with particular microbiota profiles, whereas zinc deficiency shows no such association. The nutritional intervention with the two rice treatments impacts both the composition and functions predicted from compositional analysis in different ways. (ClinicalTrials.gov (Identifier: NCT01706419)).
Topics: Humans; Oryza; Feces; Female; Male; Double-Blind Method; Child; Micronutrients; Nutritional Status; Food, Fortified; Inflammation; Gastrointestinal Microbiome; Biomarkers; Adolescent; Vitamin A; Zinc
PubMed: 38890302
DOI: 10.1038/s41467-024-49093-4 -
Immunity, Inflammation and Disease Jun 2024Triptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms...
INTRODUCTION
Triptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms underlying its effects in rheumatoid arthritis remain incompletely understood.
METHODS
Collagen-induced arthritis (CIA) model was induced in Sprague-Dawley rats by immunization with bovine type II collagen, and TP was administrated as treatment. The therapeutic effect of TP was evaluated based on paw swelling, histopathology, and serum levels of inflammatory factors. Exosomes isolated from rat serum were characterized by transmission electron microscopy, dynamic light scattering, and western blot analysis. Proteomic profiling of exosomes was analyzed by direct DIA quantitative proteomics analysis. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes databases were employed for enrichment analysis related to molecular function, biological processes, and signaling pathways. Western blot analysis was used to analyze differentially expressed proteins.
RESULTS
TP treatment ameliorated arthritic phenotypes in CIA rats as evidenced by reduced arthritis score, paw swelling, pathological injury severity scores, and serum levels of inflammatory cytokines. The proteomic analysis revealed that TP treatment significantly inhibited complement and coagulation cascades, interleukin-17 signaling pathway, and cholesterol metabolism, which were reactivated in CIA rats. Importantly, lipocalin 2 (LCN2) and myeloperoxidase (MPO) levels were markedly upregulated in the CIA group but suppressed upon TP administration. Furthermore, in synovial tissues, LCN2 and MPO expression levels were also elevated in the CIA group but decreased following TP treatment.
CONCLUSION
Our findings demonstrate that TP alleviates CIA, possibly through modulation of exosomal LCN2 and MPO proteins.
Topics: Animals; Epoxy Compounds; Phenanthrenes; Diterpenes; Arthritis, Experimental; Rats; Proteomics; Exosomes; Rats, Sprague-Dawley; Male; Arthritis, Rheumatoid; Signal Transduction; Disease Models, Animal
PubMed: 38888462
DOI: 10.1002/iid3.1322 -
Cancer Medicine Jun 2024Penile cancer (PC) is a lethal malignancy with no effective prognostic biomarker. We aim to investigate associations between trajectories of squamous cell carcinoma...
Trajectories of squamous cell carcinoma antigen and outcomes of patients with advanced penile cancer after chemotherapy based on paclitaxel, ifosfamid, and cisplatin regimen.
INTRODUCTION
Penile cancer (PC) is a lethal malignancy with no effective prognostic biomarker. We aim to investigate associations between trajectories of squamous cell carcinoma antigen (SCC-A) and patient outcomes after chemotherapy based on paclitaxel, ifosfamid, and cisplatin (TIP) regimen.
METHODS
Consecutive AJCC staging III/IV PC patients who received TIP chemotherapy and repeated SCC-A measurements in 2014-2022 were analyzed. Latent class growth mixed (LCGM) models were employed to characterize patients' serum SCC-A trajectories. Patient survival, and clinical and pathological tumor responses were compared. Inverse probability treatment weighting was used to adjust confounding factors.
RESULTS
Eighty patients were included. LCGM models identified two distinct trajectories of SCC-A: low-stable (40%; n = 32) and high-decline (60%; n = 48). Overall survival (HR [95% CI]: 3.60 [1.23-10.53], p = 0.019), progression-free survival (HR [95% CI]: 11.33 [3.19-40.3], p < 0.001), objective response rate (37.5% vs. 62.5% p = 0.028), disease control rate (60.4% vs. 96.9% p < 0.00), and pathological complete response rate (21.2% vs. 51.9%, p = 0.014) were significantly worse in the high-decline arm.
CONCLUSION
PC patients' SCC-A change rate was associated with tumor response and patient survival after TIP chemotherapy. SCC-A might assist tumor monitoring after systemic therapies.
Topics: Humans; Male; Penile Neoplasms; Middle Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Paclitaxel; Cisplatin; Serpins; Aged; Neoplasm Staging; Biomarkers, Tumor; Prognosis; Retrospective Studies; Adult
PubMed: 38888362
DOI: 10.1002/cam4.7353 -
Beilstein Journal of Organic Chemistry 2024Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, and , based...
Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, and , based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form - and -eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the -eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.
PubMed: 38887579
DOI: 10.3762/bjoc.20.115