-
EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Environment International Jun 2024As the COVID-19 pandemic has progressed, increasing evidences suggest that the gut microbiota may play a crucial role in the effectiveness of SARS-CoV-2 vaccine. Thus,...
As the COVID-19 pandemic has progressed, increasing evidences suggest that the gut microbiota may play a crucial role in the effectiveness of SARS-CoV-2 vaccine. Thus, this study was aimed at investigating the influence of SARS-CoV-2 vaccine on the gut microbiota and short-chain fatty acids (SCFAs) of organisms exposed to environmental contaminants, i.e., plasticizers: phthalate esters. We found that in mice, exposure to dioctyl terephthalate (DOTP) and bis -2-ethylhexyl phthalate (DEHP) decreased the blood glucose level and white fat weight, induced inflammatory responses, caused damage to liver and intestinal tissues, and disrupted the gut microbiota composition and SCFAs metabolism. Specifically, the Bacteroidetes phylum was positively correlated with BBIBP-CorV vaccine, while acetic acid was negatively associated with the vaccine. Interestingly, the BBIBP-CorV vaccine somewhat alleviated tissue inflammation and reduced the contents of acetic acid and propionic acid in mice exposed to DEHP and DOTP. These findings were confirmed by a fecal microbiota transplantation assay. Overall, this study revealed that exposure to DEHP and DOTP adversely affects the gut microbiota and SCFAs, while the BBIBP-CorV vaccine can protect mice against these effects. This work highlighted the relationship between BBIBP-CorV vaccination, gut microbiome composition, and responses to plasticizers, which may facilitate the development and risk assessment of SARS-CoV-2 vaccines and environmental contaminants on microbiota health.
PubMed: 38941942
DOI: 10.1016/j.envint.2024.108851 -
Molecular Genetics and Metabolism Jun 2024Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary...
Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.
PubMed: 38941880
DOI: 10.1016/j.ymgme.2024.108516 -
Comparative Biochemistry and... Jun 2024Cipangopaludina chinensis, as a financially significant species in China, represents a gastropod in nature which frequently encounters starvation stress owing to its...
Comparative physiological, biochemical and transcriptomic analyses to reveal potential regulatory mechanisms in response to starvation stress in Cipangopaludina chinensis.
Cipangopaludina chinensis, as a financially significant species in China, represents a gastropod in nature which frequently encounters starvation stress owing to its limited prey options. However, the underlying response mechanisms to combat starvation have not been investigated in depth. We collected C. chinensis under several times of starvation stress (0, 7, 30, and 60 days) for nutrient, biochemical characteristics and transcriptome analyses. The results showed that prolonged starvation stress (> 30 days) caused obvious fluctuations in the nutrient composition of snails, with dramatic reductions in body weight, survival and digestive enzyme activity (amylase, protease, and lipase), and markedly enhanced the antioxidant enzyme activities of the snails. Comparative transcriptome analyses revealed 3538 differentially expressed genes (DEGs), which were significantly associated with specific starvation stress-responsive pathways, including oxidative phosphorylation and alanine, aspartate, and glutamate metabolism. Then, we identified 40 candidate genes (e.g., HACD2, Cp1, CYP1A2, and GPX1) response to starvation stress through STEM and WGCNA analyses. RT-qPCR verified the accuracy and reliability of the high-throughput sequencing results. This study provides insights into snail overwintering survival and the potential regulatory mechanisms of snail adaptation to starvation stress.
PubMed: 38941864
DOI: 10.1016/j.cbd.2024.101279 -
Clinical Nutrition (Edinburgh, Scotland) Jun 2024An increasing amount of evidence suggests that migraine is a response to cerebral energy deficiencies or oxidative stress levels that exceed antioxidant capacity....
BACKGROUND
An increasing amount of evidence suggests that migraine is a response to cerebral energy deficiencies or oxidative stress levels that exceed antioxidant capacity. Current pharmacological options are inadequate in treating patients with chronic migraine, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. The ketogenic diet, mimicking fasting that leads to an elevation of ketone bodies, is a therapeutic intervention targeting cerebral metabolism that has recently shown great promise in the prevention of migraines. Moreover, Mediterranean elements like vegetables, nuts, herbs, spices, and olive oil that are sources of anti-inflammatory elements (omega-3 fatty acids, polyphenols, vitamins, essential minerals, and probiotics) may create a positive brain environment by reducing imbalance in the gut microbiome.
METHODS
On the basis of these indications, a combined Mediterranean-ketogenic diet was administered to chronic migraine patients for 4 (T1) and 8 weeks (T2), and anthropometric estimations were collected at T1 and T2 while biochemical parameters at only T2.
RESULTS
A significant reduction (p < 0.01) in migraine frequency and intensity was detected as early as 4 weeks of dietary intervention, which was associated with a reduced fat mass (p < 0.001) as well as Homa index (p < 0.05) and insulin levels (p < 0.01) after 8 weeks.
CONCLUSION
Overall, Mediterranean-ketogenic diet may be considered an effective non-pharmacological intervention for migraine, with positive outcomes on body composition.
PubMed: 38941791
DOI: 10.1016/j.clnu.2024.06.015 -
Poultry Science Jun 2024Periplaneta americana residue is a byproduct of using Periplaneta americana in pharmaceutical research and development for extracting active ingredients. Three hundred...
Periplaneta americana residue is a byproduct of using Periplaneta americana in pharmaceutical research and development for extracting active ingredients. Three hundred Three-yellow chickens were selected for the experiment and randomly divided into 6 groups (5 replications per group, 10 chickens per replicate): the control group (group A) was fed a basal ration, and the experimental groups (groups B, C, D, E, and F) were fed experimental diets in which P. americana residue replaced puffed soybean meal at proportions of 20, 40, 60, 80, and 100%, respectively, for a period of 42 d. The aim was to assess the impact of different levels of P. americana residue on the growth, survival, intestinal morphology, digestive enzyme activity, intestinal flora, and intestinal transcriptional responses of Three-yellow chickens. The results indicated that the increase in P. americana residue levels had a linear and quadratic impact on the average daily gain (ADG) and feed conversion ratio (FCR), respectively. The ADG was notably greater in the 40% group than in the 100% group, while the FCR was significantly lower in the 20% and 40% groups than in the 100% group (P < 0.05). Protease, lipase, and amylase activities exhibited a quadratic increase with increasing concentrations of P. americana residue (P < 0.05). Protease and lipase activities were notably greater in the 20% and 40% groups than in the 0% group (control group), amylase activity was significantly greater in the 40% group than in the 0% group (control group) (P < 0.05). Duodenal crypt depth (CD) decreased quadratically with increasing P. americana residue (P < 0.05). The duodenal villus height/crypt depth ratio (V/C) was significantly lower in the 100% group than in the 60% group (P < 0.05). The intestinal villus height (VH) increased quadratically with increasing levels of P. americana residue. The VH in the 60% group was significantly greater than that in the 0% (control group), 20, 80, and 100% groups (P < 0.05). The Chao and Ace indices demonstrated linear and quadratic increases with increasing levels of P. americana residue, while the Pd index showed a quadratic increase with increasing levels of P. americana residue (P < 0.05). The relative abundance profile of Lactobacillus exhibited a linear and quadratic decrease with increasing levels of P. americana residue, with the 100% group showing a significantly lower abundance than the 0% (control group) and 40% groups (P < 0.05). The transcriptome results showed that P. americana residue could enhance the digestive system by promoting vitamin, fat, carbohydrate digestion and absorption, cholesterol metabolism, etc. In conclusion, P. americana residue can replace puffed soybean meal without negatively affecting the growth performance of three-yellow chickens. The low and medium groups had positive effects on the growth performance, digestive enzyme activity, intestinal morphology, intestinal flora, and substance digestion and absorption of three-yellow chickens. The recommended replacement of P. americana residue for puffed soybean meal in the diets of three-yellow chickens ranged from 20% to 60%.
PubMed: 38941789
DOI: 10.1016/j.psj.2024.103967 -
Poultry Science Jun 2024The late embryonic development of the liver, a major metabolic organ, remains poorly characterized at single cell resolution. Here, we used single-nucleus RNA-sequencing...
The late embryonic development of the liver, a major metabolic organ, remains poorly characterized at single cell resolution. Here, we used single-nucleus RNA-sequencing (snRNA-seq) to characterize the chicken liver cells at 2 embryonic development time points (E14 and D1). We uncovered 8 cell types including hepatocytes, endothelial cells, hepatic stellate cells, erythrocytes, cholangiocytes, kupffer cells, mesothelial cells, and lymphocytes. And we discovered significant differences in the abundance of different cell types between E14 and D1. Moreover, we characterized the heterogeneity of hepatocytes, endothelial cells, and mesenchymal cells based on the gene regulatory networks of each clusters. Trajectory analyses revealed 128 genes associated with hepatocyte development and function, including apolipoprotein genes involved hepatic lipid metabolism and NADH dehydrogenase subunits involved hepatic oxidative phosphorylation. Furthermore, we identified the differentially expressed genes (DEGs) between E14 and D1 at the cellular levels, which contribute to changes in liver development and function. These DEGs were significantly enriched in PPAR signaling pathways and lipid metabolism related pathways. Our results presented the single-cell mapping of chick embryonic liver at late stages of development and demonstrated the metabolic changes across the 2 age stages at the cellular level, which can help to further study the molecular development mechanism of embryonic liver.
PubMed: 38941785
DOI: 10.1016/j.psj.2024.103979 -
Journal of Chromatography. B,... Jun 2024Pig bile- and Fructus Evodiae sauce-processed Rhizoma Coptidis (Danhuanglian, DHL; Yuhuanglian, YHL, respectively) are two types of processed Rhizoma Coptidis...
Integrated metabolomics and network pharmacology analysis to explore pig bile-processed Rhizoma Coptidis and Fructus Evodiae sauce-processed Rhizoma Coptidis in lipopolysaccharide-induced inflammatory response.
Pig bile- and Fructus Evodiae sauce-processed Rhizoma Coptidis (Danhuanglian, DHL; Yuhuanglian, YHL, respectively) are two types of processed Rhizoma Coptidis (Huanglian, HL) in traditional Chinese medicine (TCM). DHL and YHL are representative of HL generated from the subordinate and counter system processing methods, respectively, both noted for their anti-inflammatory effects. How these processing methods can affect the medicinal efficacy of HL remains a hot topic. Here, we discussed the influence of the two methods on the efficacy of final HL products (i.e., DHL and YHL) by comparing their components and anti-inflammatory mechanisms. Enzyme-linked immunosorbent assay was employed to measure inflammatory factors in RAW264.7 cells induced by lipopolysaccharide, and UPLC-Q-Exactive Orbitrap-MS was utilized to analyze the endogenous differential metabolites of RAW264.7 cells treated with HL, YHL, and DHL, and thus to identify the related metabolic pathways. Finally, using network pharmacology, we constructed a "disease-target-differential metabolites-active ingredients" network map. Compared with the control, all three products, HL, YHL, and DHL, significantly reduced IL-6, TNF-α, and IL-1β levels. 12 differential metabolites related to inflammation were identified and 25 target proteins were overlapping among the three groups. Notably, the anti-inflammatory effects of DHL and YHL were mediated by metabolic pathways such as aminoacyl-tRNA biosynthesis, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and arginine biosynthesis. Specifically, DHL significantly impacted free fatty acid levels, which was not observed with HL and YHL. On screening, DHL had 9 active ingredients, including three from pig bile, and YHL had 12 active ingredients, with six from the processing excipient Fructus Evodiae. The distinct anti-inflammatory mechanisms and material basis of YHL and DHL were characterized by consistency and distinctiveness. Thus, this study underscores the significant influence of processing methods on the medicinal efficacy of TCMs by revealing their regulatory mechanisms and material bases.
PubMed: 38941716
DOI: 10.1016/j.jchromb.2024.124192 -
The Journal of Surgical Research Jun 2024Glucagon-like peptide-1 receptor agonist (GLP-1A) medications are gaining widespread popularity for the treatment of obesity. The optimal use of these drugs in pediatric...
INTRODUCTION
Glucagon-like peptide-1 receptor agonist (GLP-1A) medications are gaining widespread popularity for the treatment of obesity. The optimal use of these drugs in pediatric bariatric populations, and especially in those considering metabolic and bariatric surgery (MBS), is yet to be established. We sought to characterize current practice patterns of GLP-1A use at major pediatric bariatric centers across the United States.
MATERIALS AND METHODS
We administered an online survey to a purposive sample of 46 surgeons who perform MBS on children and adolescents. Survey questions explored practices prescribing GLP-1As in patients considering MBS, holding them prior to elective operations, and restarting them postoperatively following MBS. Responses were summarized with descriptive statistics and inductive content analysis.
RESULTS
There were 22 responses (48% response rate) representing 19 institutions. Most (86%) respondents do sometimes prescribe GLP-1As for patients considering MBS, but the specific indications vary. Practices for holding GLP-1As preoperatively also vary, from not at all to holding for 2 wk. Over half (55%) of respondents sometimes restart GLP-1As after MBS. Free-response themes included still-evolving preoperative utilization patterns, difficulty with access and insurance coverage, and a lack of data informing GLP-1A use in the pre and postoperative periods.
CONCLUSIONS
Given the increasing use of these medications for weight loss purposes, this substantial variation in practice highlights a need for further research to examine the safest and most effective use of GLP-1As in the pre and postoperative periods and for practice guidelines to standardize care pathways in pediatric bariatric contexts.
PubMed: 38941713
DOI: 10.1016/j.jss.2024.05.045 -
Clinical and Translational Medicine Jul 2024Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic... (Review)
Review
BACKGROUND
Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor-mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic-targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis.
MAIN BODY AND CONCLUSION
Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment.
KEY POINTS
Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic-targeted drugs offer valuable clinical options for cancer therapy.
Topics: Humans; Serotonin; Neoplasms; Signal Transduction
PubMed: 38943041
DOI: 10.1002/ctm2.1750