De novo mutations promote inflammation in children with STAT3 gain-of-function syndrome by affecting IL-1ß expression.

STAT3 gain-of-function syndrome, characterized by early-onset autoimmunity and primary immune regulatory disorder, remains poorly understood in terms of its immunological mechanisms. We employed whole-genome sequencing of familial trios to elucidate the pivotal role of de novo mutations in genetic diseases. We identified 37 high-risk pathogenic loci affecting 23 genes, including a novel STAT3 c.508G>A mutation. We also observed significant down-regulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c. These findings enhance our understanding of the pathogenesis of STAT3 gain-of-function syndrome and suggest potential therapeutic strategies. Notably, combined JAK inhibitors and IL-6R antagonists may offer promising treatment avenues for mitigating the severity of STAT3 gain-of-function syndrome.

Identification of Dendrobium Using Laser-Induced Breakdown Spectroscopy in Combination with a Multivariate Algorithm Model.

Dendrobium, a highly effective traditional Chinese medicinal herb, exhibits significant variations in efficacy and price among different varieties. Therefore, achieving an efficient classification of Dendrobium is crucial. However, most of the existing identification methods for Dendrobium make it difficult to simultaneously achieve both non-destructiveness and high efficiency, making it challenging to truly meet the needs of industrial production. In this study, we combined Laser-Induced Breakdown Spectroscopy (LIBS) with multivariate models to classify 10 varieties of Dendrobium. LIBS spectral data for each Dendrobium variety were collected from three circular medicinal blocks. During the data analysis phase, multivariate models to classify different Dendrobium varieties first preprocess the LIBS spectral data using Gaussian filtering and stacked correlation coefficient feature selection. Subsequently, the constructed fusion model is utilized for classification. The results demonstrate that the classification accuracy of 10 Dendrobium varieties reached 100%. Compared to Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), our method improved classification accuracy by 14%, 20%, and 20%, respectively. Additionally, it outperforms three models (SVM, RF, and KNN) with added Principal Component Analysis (PCA) by 10%, 10%, and 17%. This fully validates the excellent performance of our classification method. Finally, visualization analysis of the entire research process based on t-distributed Stochastic Neighbor Embedding (t-SNE) technology further enhances the interpretability of the model. This study, by combining LIBS and machine learning technologies, achieves efficient classification of Dendrobium, providing a feasible solution for the identification of Dendrobium and even traditional Chinese medicinal herbs.

Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease.

GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

Effect of miR-1297 on Kidney Injury in Rats with Diabetic Nephropathy through the PTEN/PI3K/AKT Pathway.

PURPOSE: This study aimed to determine the influence of miR-1297 on kidney injury in rats with diabetic nephropathy (DN) and its causal role. METHODS: A DN rat model was established through right kidney resection and intraperitoneal injection of streptozotocin (STZ). Sham rats did not undergo right kidney resection or STZ injection. The DN rats were divided into the DN model and antagomiR-1297 treatment groups. Kidney morphology was observed using hematoxylin and eosin staining. Renal function indices, including blood urea nitrogen (BUN), serum creatinine (SCr), and urinary protein, were measured using kits. Levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined through enzyme-linked immunosorbent assay (ELISA). Fibrin (FN), collagen type I (Col I), and α-smooth muscle actin (α-SMA) were assessed through western blotting and real-time reverse transcription-polymerase chain reaction. Apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. miR-1297 targets were predicted using bioinformatic software and verified through luciferase reporter assay. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway expression was analyzed through western blotting. RESULTS: AntagomiR-1297 reduced BUN (p = 0.005), SCr (p = 0.012), and urine protein (p < 0.001) levels and improved kidney tissue morphology. It prevented renal interstitial fibrosis by decreasing FN, Col I, and α-SMA protein levels (all p < 0.001). AntagomiR-1297 increased SOD (p = 0.001) and GSH-Px (p = 0.002) levels. Additionally, it reduced levels of cell inflammatory factors, including TNF-α, IL-6, and IL-1ß (all p < 0.001), and alleviated apoptosis (p < 0.001) in rat kidney tissue with DN. miR-1297 was pinpointed as a target for PTEN. AntagomiR-1297 increased PTEN expression and suppressed PI3K and AKT phosphorylation (all p < 0.001). CONCLUSIONS: AntagomiR-1297 can mitigate renal fibrosis, renal inflammation, apoptosis, and oxidative stress levels through the PTEN/PI3K/AKT pathway.

CBD and THC in Special Populations: Pharmacokinetics and Drug-Drug Interactions.

Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug-drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated. While some clinical trials have explored DDIs between therapeutic drugs like antiepileptic drugs and CBD/THC, more potential interactions remain to be examined. This review summarizes the published studies on CBD and THC-drug interactions, outlines the mechanisms involved, discusses the physiological considerations in pharmacokinetics (PK) and DDI studies in special populations (including pregnant and lactating women, pediatrics, older adults, patients with hepatic or renal impairments, and others), and presents modeling approaches that can describe the DDIs associated with CBD and THC in special populations. The PK of CBD and THC in special populations remain poorly characterized, with limited studies investigating DDIs involving CBD/THC in these populations. Therefore, it is critical to evaluate potential DDIs between CBD/THC and medications that are commonly used in special populations. Modeling approaches can aid in understanding these interactions.

Structural and functional investigation on stem and peel polysaccharides from different varieties of pitaya.

Varieties of plant species may affect the composition and structures of the polysaccharides, thus have an impact on their chemical properties and biological activities. Herein, the present study comparatively evaluated the differences in the chemical composition, morphological structures, antioxidant activity, and anti-inflammatory activity of the stem and peel polysaccharides from different varieties of pitaya. The FT-IR and NMR spectra indicated that the six polysaccharides had similar structural features, whereas the physicochemical characterization showed that they differed significantly in terms of the monosaccharide composition, molecular weight, and surface morphology. In addition, different varieties of pitaya polysaccharides exhibited different antioxidant activities and similar anti-inflammatory activities. These data suggested that varietal differences resulted in pitaya stem and peel polysaccharides with different monosaccharide compositions and molecular weights, thus led to different antioxidant activities and protection against oxidative damage, while similar structural features were closely related to their similar anti-inflammatory activities. Therefore, the study of the stem and peel polysaccharides from different varieties of pitaya can help us to better understand the relationship between their composition and structure and their biological activities. In addition, pitaya stem and peel polysaccharides have the potential to act as antioxidants or to treat inflammatory damage.

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.

Changes of FGF23 and hearing in chronic renal failure and their correlation analysis.

BACKGROUND: To explore the association between fibroblast growth factor 23 (FGF23) and hearing in chronic renal failure (CRF). METHODS: Pure tone audiometry was used to detect the hearing of patients with CRF; the level of serum FGF23, creatinine, blood urea nitrogen (BUN), parathyroid hormone (PTH), and mean binaural hearing threshold were compared to the control group (people without kidney disease). The rat model of renal failure was established by 5/6 nephrectomy, and the auditory brainstem response (ABR) of rats after modeling was detected by the Tucker Davis Technologies (TDT) system; the expression level of FGF23 in the peripheral blood, renal and cochlear tissue was also detected. RESULTS: The incidence of hearing loss (HL) and serum FGF23 were higher in CRF patients than the control group; the sFGF23 was positively correlated with the mean binaural hearing threshold. Animal studies showed that the ABR threshold, creatinine, FGF23, BUN, and PTH increased after modeling; although, an increase in FGF23 was observed earlier than other indicators. The HL of rats with renal failure was significantly correlated with BUN, phosphate, PTH, sFGF23, kFGF23/ß-actin, eFGF23/ß-actin, weight, and modeling cycle. CONCLUSIONS: Both CRF patients and rat models showed high-frequency HL. FGF23 was highly expressed in the serum of HL renal failure patients and rats, as well as in the renal tissue and cochlea of renal failure rats. Therefore, FGF23 may be involved in the occurrence and development of HL caused by CRF.

Effect of Oregon grape root extracts on P-glycoprotein mediated transport in in vitro cell lines.

Purpose: This study aims to investigate the potential of Oregon grape root extracts to modulate the activity of P-glycoprotein. Methods: We performed 3H-CsA or 3H-digoxin transport experiments in the absence or presence of two sources of Oregon grape root extracts (E1 and E2), berberine or berbamine in Caco-2 and MDCKII-MDR1 cells. In addition, real time quantitative polymerase chain reaction (RT-PCR) was performed in Caco-2 and LS-180 cells to investigate the mechanism of modulating P-glycoprotein. Results: Our results showed that in Caco-2 cells, Oregon grape root extracts (E1 and E2) (0.1-1 mg/mL) inhibited the efflux of CsA and digoxin in a dose-dependent manner. However, 0.05 mg/mL E1 significantly increased the absorption of digoxin. Ten µM berberine and 30 µM berbamine significantly reduced the efflux of CsA, while no measurable effect of berberine was observed with digoxin. In the MDCKII-MDR1 cells, 10 µM berberine and 30 µM berbamine inhibited the efflux of CsA and digoxin. Lastly, in real time RT-PCR study, Oregon grape root extract (0.1 mg/mL) up-regulated mRNA levels of human MDR1 in Caco-2 and LS-180 cells at 24 h. Conclusion: Our study showed that Oregon grape root extracts modulated P-glycoprotein, thereby may affect the bioavailability of drugs that are substrates of P-glycoprotein.