Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models

Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple toxicity parameters of BASR-pCHM would provide critical reference and guidelines for their safe clinical application. Examination of standardized extracts from 58 compound BASR-pCHM in vivo in VEGFR2-luc mice and in vitro in cardiac, renal, and hepatic cells identified Naoluotong capsule (NLTC) as a potent organ/cell damage inducer. Composition analysis revealed that NLTC was the one that contained nonherbal ingredients among the BASR-pCHM collection. In vivo and in vitro experiments confirmed that NLTC, as well as its chemical supplement tolperisone hydrochloride, caused organ and cell damage by reducing cell viability, mitochondrial mass/activity, while the NLTC herbal components did not. Taken together, our study showed that safety evaluation of patent herbal medicines already on market is still necessary and urgently needed. In addition, chemical/herbal interactions should be considered as an important contributor of potential toxicity when evaluating the safety of herbal medicine

KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma

Abstract Background Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs. Case presentation Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL. Conclusions This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.https://deepblue.lib.umich.edu/bitstream/2027.42/145736/1/13000_2018_Article_758.pd

Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm

全身の体内リズムを調和させるRNA配列の発見 --体温の日内変化に合わせてしなやかに調和させる--. 京都大学プレスリリース. 2023-03-07.Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C–38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5′ UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

MLE with datasets from populations having shared parameters

We consider maximum likelihood estimation with two or more datasets sampled from different populations with shared parameters. Although more datasets with shared parameters can increase statistical accuracy, this paper shows how to handle heterogeneity among different populations for correctness of estimation and inference. Asymptotic distributions of maximum likelihood estimators are derived under either regular cases where regularity conditions are satisfied or some non-regular situations. A bootstrap variance estimator for assessing performance of estimators and/or making large sample inference is also introduced and evaluated in a simulation study

Trade-Off Between Light Deprivation and Desiccation in Intertidal Seagrasses Due To Periodic Tidal Inundation and Exposure: Insights From a Data-Calibrated Model

Some seagrass species thrive in shallow intertidal zones globally, adapting to periodic tidal inundation and exposure with distinctive physiological traits and offering crucial ecosystem services. However, predicting the responses of intertidal seagrasses to external stressors is hampered by the complexity of the dynamic and harsh environments they occupy. Intertidal seagrass growth models, especially those incorporating dynamic physiological responses, are scarce in the literature. Our study comprehensively collated relevant data from the literature to parameterize the relationship between air exposure, seagrass leaf water content and photosynthetic efficiency to inform new growth rate functions for generalizable intertidal seagrass growth models. We tested the applicability of these model formulations for scenarios with varying physiological process assumptions, seagrass species, tidal conditions, meadow elevations and water turbidity. We found that neglecting air-exposed physiological responses (i.e., leaf water content loss and reduced photosynthetic efficiency) can substantially overestimate seagrass growth rates. We also observed a trade-off between light deprivation and desiccation on intertidal seagrass growth under specific tidal ranges and turbidity conditions. This can yield an “optimal” elevation where overall stress of desiccation (increasing with meadow elevation) and light deprivation (decreasing with meadow elevation) are minimized. The predicted optimal elevation, that is, the most suitable habitat for intertidal seagrass, moves upward as water turbidity increases. Our study provides conceptual and quantitative guidance for ecological modelers to include air exposure responses of intertidal seagrasses in coastal ecosystem models. The model also helps to evaluate the viability of intertidal seagrass habitats and inform decisions on coastal ecosystem management under changing environmental conditions

A bioinformatic analysis found low expression and clinical significance of ATF4 in breast cancer

Background: Activating Transcription Factor 4 (ATF4) expression exhibits differential patterns across different types of tumors. Besides, the pathogenesis of breast cancer is complex, and the exact relationship between ATF4 and ATF4 remains uncertain. Methods: The analysis of ATF4 expression was conducted by utilizing The Cancer Genome Atlas (TCGA) pan-cancer data, while the gene expression profile of breast cancer was checked by the comprehensive database-Gene Expression Omnibus database. In order to gain a more comprehensive understanding of the specific cell types that exhibit ATF4 expression within the microenvironment of breast cancer, we conducted a single-cell analysis of ATF4 using two distinct datasets of human breast cancer (GSE114717 and GSE11088, respectively). The spatial distribution of ATF4 within a tissue was demonstrated based on datasets obtained from the Human Protein Atlas (HPA) and SpatialDB. The clinical prognostic significance of ATF4 was assessed by analyzing clinical survival data obtained from TCGA, GSE4830, and GSE25055 datasets. We used the R package clusterProfiler to carry out an enrichment analysis of ATF4. We assessed how ATF4 impacts the growth and movement of breast cancer cell lines. We manipulated ATF4 levels using plasmid transfection techniques. Results: The expression of ATF4 was found to be suboptimal and demonstrated a significant correlation with enhanced disease-specific survival (p = 0.012) and overall survival (p = 0.032) in breast cancer as well as other malignancies. We conducted an analysis to investigate the interaction between the infiltration level of immune cells and the expression of ATF4, using samples obtained from TCGA with known immune cell infiltration scores. Furthermore, a notable positive correlation exists between the elevated expression of ATF4 and immune-related genomes, specifically those associated with chemokine as well as immunity. Subsequent examination revealed a notable augmentation in the cytodifferentiation of T cells into regulatory T (Treg) cells within tissues exhibiting elevated levels of ATF4 expression. ATF4 exhibits notable upregulation in the MDA-MB-231 cell, thereby exerting a substantial impact on cell proliferation and migration upon its knockdown. Conversely, the overexpression of ATF4 in the MCF7 Luminal A breast cancer cell line can also modulate cellular function. Conclusions: Our study suggests that ATF4 helps T cells differentiate into Treg cells in breast cancer. ATF4 can represent a clinically useful biomarker to predict the overall survival rate, especially in patients with different subtypes of breast cancer. Provide certain guidance value for the development of targeted drugs or inhibitors targeting ATF4

Effect of Nutrient Solution Flow Rate on Hydroponic Plant Growth and Root Morphology

Crop production under hydroponic environments has many advantages, yet the effects of solution flow rate on plant growth remain unclear. We conducted a hydroponic cultivation study using different flow rates under light-emitting diode lighting to investigate plant growth, nutrient uptake, and root morphology under different flow rates. Swiss chard plants were grown hydroponically under four nutrient solution flow rates (2 L/min, 4 L/min, 6 L/min, and 8 L/min). After 21 days, harvested plants were analyzed for root and shoot fresh weight, root and shoot dry weight, root morphology, and root cellulose and hemicellulose content. We found that suitable flow rates, acting as a eustress, gave the roots appropriate mechanical stimulation to promote root growth, absorb more nutrients, and increase overall plant growth. Conversely, excess flow rates acted as a distress that caused the roots to become compact and inhibited root surface area and root growth. Excess flow rate thereby resulted in a lower root surface area that translated to reduced nutrient ion absorption and poorer plant growth compared with plans cultured under a suitable flow rate. Our results indicate that regulating flow rate can regulate plant thigmomorphogenesis and nutrient uptake, ultimately affecting hydroponic crop quality