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Journal of Ethnopharmacology May 2024Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be...
Anchang Yuyang Decoction inhibits experimental colitis-related carcinogenesis by regulating PPAR signaling pathway and affecting metabolic homeostasis of host and microbiota.
ETHNOPHARMACOLOGICAL RELEVANCE
Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties.
AIM OF THE STUDY
This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches.
MATERIALS AND METHODS
A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting.
RESULTS
AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-β/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]).
CONCLUSIONS
This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
Topics: Rats; Animals; Mice; Peroxisome Proliferator-Activated Receptors; RNA, Ribosomal, 16S; Chromatography, Liquid; Tandem Mass Spectrometry; Colitis; Inflammation; Signal Transduction; Inflammatory Bowel Diseases; Carcinogenesis; Azoxymethane; Gastrointestinal Microbiome; Colorectal Neoplasms; Homeostasis; Adenoma; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colon
PubMed: 38428656
DOI: 10.1016/j.jep.2024.117995 -
PloS One 2024Risdiplam is a new drug for treating spinal muscular atrophy (SMA). However, pharmacovigilance analyses are necessary to objectively evaluate its safety-a crucial step...
Risdiplam is a new drug for treating spinal muscular atrophy (SMA). However, pharmacovigilance analyses are necessary to objectively evaluate its safety-a crucial step in preventing severe adverse events (AEs). Accordingly, the primary objective of the current study was to examine the AEs associated with risdiplam use based on real-world data obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. More specifically, we examined incidents reported between the third quarter of 2020 and the second quarter of 2023. The imbalance of risdiplam-related AEs was evaluated by computing the reporting odds ratio. A total of 5,406,334 reports were thoroughly reviewed. By removing duplicate reports, we identified 1588 reports in which risdiplam was the main suspected drug whose use was accompanied by 3470 associated AEs. Among the included AEs, 703 were categorized as serious and 885 as non-serious. Risdiplam use induced AEs across 18 organ systems, resulting in 130 positive signals. Notably, we detected new AE signals, including cardiac arrest, nephrolithiasis, tachycardia, loss of libido, and elevated hepatic enzyme activities; however, no ophthalmologic toxicity was reported. Although these new adverse reaction signals associated with risdiplam have been defined, long-term clinical studies are needed to confirm these findings. Nevertheless, our findings provide a valuable reference for improving the clinical management of SMA.
Topics: United States; Humans; Retrospective Studies; United States Food and Drug Administration; Azo Compounds; Databases, Factual; Muscular Atrophy, Spinal; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Pyrimidines
PubMed: 38427665
DOI: 10.1371/journal.pone.0298609 -
Scientific Reports Feb 2024Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many...
Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Oxidative Phosphorylation; Pilot Projects; Mitogen-Activated Protein Kinase Kinases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Cell Proliferation; Cell Movement; Diazomethane; Dipeptides
PubMed: 38424293
DOI: 10.1038/s41598-024-55544-1 -
Nature Communications Feb 2024Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce...
Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5' splice site sequences, suggest that branaplam recognizes 5' splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.
Topics: Humans; RNA Splicing; Azo Compounds; Oligonucleotides; Oligonucleotides, Antisense; RNA Splice Sites; Muscular Atrophy, Spinal; Pyrimidines
PubMed: 38424098
DOI: 10.1038/s41467-024-46090-5 -
CNS Neuroscience & Therapeutics Feb 2024Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to...
AIM
Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders.
METHODS
In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats.
RESULTS
Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM.
CONCLUSION
Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.
Topics: Pregnancy; Rats; Female; Animals; Haloperidol; Methylazoxymethanol Acetate; Olanzapine; Rats, Sprague-Dawley; Antipsychotic Agents; Lipids; Disease Models, Animal
PubMed: 38421095
DOI: 10.1111/cns.14565 -
Cell Reports Mar 2024The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT)...
The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.
Topics: Humans; Animals; Mice; Butyrates; Clostridiales; Azoxymethane; Colorectal Neoplasms; Rectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Receptors, G-Protein-Coupled
PubMed: 38412097
DOI: 10.1016/j.celrep.2024.113846 -
JMIR Medical Education Feb 2024Previous studies have predominantly measured e-professionalism through perceptions or attitudes, yet there exists no validated measure specifically targeting the actual...
BACKGROUND
Previous studies have predominantly measured e-professionalism through perceptions or attitudes, yet there exists no validated measure specifically targeting the actual behaviors of health care professionals (HCPs) in this realm. This study addresses this gap by constructing a normative framework, drawing from 3 primary sources to define e-professional behavior across 6 domains. Four domains pertain to the dangers of social networking sites (SNSs), encompassing confidentiality, privacy, patient interaction, and equitable resource allocation. Meanwhile, 2 domains focus on the opportunities of SNSs, namely, the proactive dissemination of public health information and maintaining scientific integrity.
OBJECTIVE
This study aims to develop and validate 2 new measures assessing the e-professional behavior of doctors of medicine (MDs) and doctors of dental medicine (DMDs), focusing on both the dangers and opportunities associated with SNSs.
METHODS
The study used a purposive sample of MDs and DMDs in Croatia who were users of at least one SNS. Data collection took place in 2021 through an online survey. Validation of both indexes used a formative approach, which involved a 5-step methodology: content specification, indicators definition with instructions for item coding and index construction, indicators collinearity check using the variance inflation factor (VIF), external validity test using multiple indicators multiple causes (MIMIC) model, and external validity test by checking the relationships of the indexes with the scale of attitude toward SNSs using Pearson correlation coefficients.
RESULTS
A total of 753 responses were included in the analysis. The first e-professionalism index, assessing the dangers associated with SNSs, comprises 14 items. During the indicators collinearity check, all indicators displayed acceptable VIF values below 2.5. The MIMIC model showed good fit (χ=9.4, P=.742; χ/df=0.723; root-mean-square error of approximation<.001; goodness-of-fit index=0.998; comparative fit index=1.000). The external validity of the index is supported by a statistically significant negative correlation with the scale measuring attitudes toward SNSs (r=-0.225, P<.001). Following the removal of 1 item, the second e-professionalism index, focusing on the opportunities associated with SNSs, comprises 5 items. During the indicators collinearity check, all indicators exhibited acceptable VIF values below 2.5. Additionally, the MIMIC model demonstrated a good fit (χ=2.5, P=.718; χ/df=0.637; root-mean-square error of approximation<0.001; goodness-of-fit index=0.999; comparative fit index=1.000). The external validity of the index is supported by a statistically significant positive correlation with the scale of attitude toward SNSs (r=0.338; P<.001).
CONCLUSIONS
Following the validation process, the instrument designed for gauging the e-professional behavior of MDs and DMDs consists of 19 items, which contribute to the formation of 2 distinct indexes: the e-professionalism index, focusing on the dangers associated with SNSs, comprising 14 items, and the e-professionalism index, highlighting the opportunities offered by SNSs, consisting of 5 items. These indexes serve as valid measures of the e-professional behavior of MDs and DMDs, with the potential for further refinement to encompass emerging forms of unprofessional behavior that may arise over time.
Topics: Humans; Azo Compounds; Correlation of Data; Croatia; Data Collection
PubMed: 38412021
DOI: 10.2196/50156 -
Journal of Controlled Release :... Apr 2024Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor...
Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity.
Topics: Animals; Mice; Diazooxonorleucine; Prodrugs; Glutamine; Colonic Neoplasms; Oxidation-Reduction; Tumor Microenvironment
PubMed: 38403173
DOI: 10.1016/j.jconrel.2024.02.031 -
International Journal of Molecular... Feb 2024Diamide insecticides have always been a hot research topic in the field of pesticides. To further discover new compounds with high activity and safety, indane and its...
Diamide insecticides have always been a hot research topic in the field of pesticides. To further discover new compounds with high activity and safety, indane and its analogs were introduced into chlorantraniliprole, and a battery of chlorfenil derivatives, including indane and its analogs, were designed and prepared for biological testing. Their characterization and verification were carried out through nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Biological detection showed that all the compounds exhibited good insecticidal activity against At 0.8 mg/L, the insecticidal activity of compound against was 80%, which was slightly better than that of chlorantraniliprole. The results of the structure-activity relationship (SAR) analysis indicated that the indane moiety had a significant effect on insecticidal activity, especially in the R-configuration. The results indicated that chlorantraniliprole derivatives containing indane groups could serve as pilot compounds for the further development of new insecticides.
Topics: Animals; Insecticides; Diamide; Drug Design; Structure-Activity Relationship; Moths; Molecular Structure; ortho-Aminobenzoates
PubMed: 38397120
DOI: 10.3390/ijms25042445 -
PloS One 2024The fall armyworm (Spodoptera frugiperda) is one of the most destructive pests of corn. New infestations have been reported in the East Hemisphere, reaching India,...
Characterization of the inheritance of field-evolved resistance to diamides in the fall armyworm (Spodoptera frugiperda) (Lepidoptera: Noctuidae) population from Puerto Rico.
The fall armyworm (Spodoptera frugiperda) is one of the most destructive pests of corn. New infestations have been reported in the East Hemisphere, reaching India, China, Malaysia, and Australia, causing severe destruction to corn and other crops. In Puerto Rico, practical resistance to different mode of action compounds has been reported in cornfields. In this study, we characterized the inheritance of resistance to chlorantraniliprole and flubendiamide and identified the possible cross-resistance to cyantraniliprole and cyclaniliprole. The Puerto Rican (PR) strain showed high levels of resistance to flubendiamide (RR50 = 2,762-fold) and chlorantraniliprole (RR50 = 96-fold). The inheritance of resistance showed an autosomal inheritance for chlorantraniliprole and an X-linked inheritance for flubendiamide. The trend of the dominance of resistance demonstrated an incompletely recessive trait for H1 (♂ SUS × ♀ PR) × and an incompletely dominant trait for H2 (♀ SUS × ♂ PR) × for flubendiamide and chlorantraniliprole. The PR strain showed no significant presence of detoxification enzymes (using synergists: PBO, DEF, DEM, and VER) to chlorantraniliprole; however, for flubendiamide the SR = 2.7 (DEM), SR = 3.2 (DEF) and SR = 7.6 (VER) indicated the role of esterases, glutathione S- transferases and ABC transporters in the metabolism of flubendiamide. The PR strain showed high and low cross-resistance to cyantraniliprole (74-fold) and cyclaniliprole (11-fold), respectively. Incomplete recessiveness might lead to the survival of heterozygous individuals when the decay of diamide residue occurs in plant tissues. These results highlight the importance of adopting diverse pest management strategies, including insecticide rotating to manage FAW populations in Puerto Rico and other continents.
Topics: Humans; Animals; Spodoptera; Diamide; Puerto Rico; Insecticide Resistance; Moths; Insecticides; Larva; Fluorocarbons; ortho-Aminobenzoates; Pyrazoles; Phthalimides; Sulfones
PubMed: 38394153
DOI: 10.1371/journal.pone.0295928