Enhanced oral bioavailability of cannabidiol by flexible zein nanoparticles: in vitro and pharmacokinetic studies.

Introduction: Cannabidiol (CBD) has a variety of pharmacological effects including antiepileptic, antispasmodic, anxiolytic and anti-inflammatory among other pharmacological effects. However, since CBD is a terpene-phenolic compound, its clinical application is limited by its poor water solubility, low stability, and low bioavailability. Methods: In this study, we used several strategies to address the above problems. Hydrochloric acid was used to modify zein to improve the molecular flexibility. Flexible zein nanoparticles (FZP-CBD) loaded with CBD was prepared to improve the stability and bioavailability of CBD. The parameters were evaluated in terms of morphology, particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), loading capacity (LC%), and storage stability. Simulated gastrointestinal fluid release experiment and bioavailability assay were applied in the evaluation. Results: The simulated gastrointestinal fluid experiment showed that the release rates of FZP-CBD and natural zein nanoparticles (NZP-CBD) loaded with CBD were 3.57% and 89.88%, respectively, after digestion with gastric fluid for 2 h, 92.12% and 92.56%, respectively, after intestinal fluid digestion for 2 h. Compared with NZP-CBD, the C max of FZP-CBD at 3 different doses of CBD was increased by 1.7, 1.3 and 1.5 times respectively, and AUC0-t was increased by 1.4, 1.1 and 1.7 times respectively, bioavailability (F) was increased by 135.9%, 114.9%, 169.6% respectively. Discussion: The experimental results showed that FZP-CBD could protect most of the CBD from being released in the stomach, and then control its release in the intestines, promote the absorption of CBD in the small intestine, and increase the bioavailability of CBD. Therefore, FZP-CBD could improve the utilization value of CBD and provide a new idea for the application of CBD in medicine and pharmacy.

Novel Stability Criteria of Asynchronously Switched Nonlinear Neutral Time-Delay Systems.

This article investigates the input-to-state stability and integral input-to-state stability for the switched nonlinear neutral systems (SNNSs) with multiple time-varying delays (MTVDs) and asynchronous switching. According to the fact that the switching signals of the controllers and the subsystems are inconsistent, novel stability criteria on the input-to-state stability and integral input-to-state stability properties for SNNSs with MTVDs and the asynchronous switching phenomenon are presented by multiple Lyapunov-Krasovskii functionals, the merging switching signal, and the mode-dependent average dwell time technique. Compared with the existing related works, our results are less conservative. Meanwhile, our proposed works not only investigate the effects of switches and neutral terms on the stability property for SNNSs but also study the case of the systems with MTVDs and asynchronous switching. Finally, two practical examples, including the practical coupled mass-spring-damper-pendulum system, are presented to show the effectiveness of our results.

Cancer-associated fibroblasts derived exosomal LINC01833 promotes the occurrence of non-small cell lung cancer through miR-335-5p -VAPA axis.

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME) and can induce functional polarization of tumor macrophages. This study aimed to explore the effect of CAFs-derived exosome LINC01833 on the malignant biological behavior of non-small cell lung cancer (NSCLC) cells and its mechanism. Tumor tissues (n = 3) and adjacent noncancerous tissues (n = 3) were collected from patients with NSCLC, and fibroblasts (CAF, NF) were isolated from the two tissues. Expression of LINC01833/miR-335-5p/VAPA in NSCLC clinical tissues and cell lines was detected by RT-qPCR. Exosomes of CAFs and NFs were isolated by ultracentrifugation. Cell proliferation, migration, invasion, and M2 macrophage polarization were detected by MTT, transwell, wound-healing assay, and flow cytometry assay, while western blot was used to verify the expression of M2 macrophage polarization-related proteins. Tumor volume weight and M2 macrophage polarization were detected by tumor xenografts in nude mice. LINC01833 was highly expressed in NSCLC tumor tissues and cells. Knockdown of LINC01833 exosomes could significantly inhibit proliferation, migration, invasion of NSCLC cells, and M2 macrophage polarization of THP-1 cells, while simultaneous knockdown of miR-335-5p on the above basis could reverse the effect of knockdown of LINC01833. In vivo experiments also indicated that knockdown of LINC01833 exosomes suppressed tumor growth and M2 macrophage polarization. CAF-derived LINC01833 exosomes can promote the proliferation, migration and invasion of NSCLC cells and M2 macrophage polarization by inhibiting miR-335-5p and regulating VAPA activity.

Long-term and low-dose rituximab treatment for chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To evaluate the efficacy and safety of a low-dose, long-term rituximab regimen in the treatment of idiopathic CIDP. METHODS: This study included 15 CIDP patients treated with rituximab. Patients were administered 600 mg of rituximab intravenously every 6 months. Baseline evaluation was conducted before the initiation of rituximab treatment and subsequent evaluations were conducted 6 months after each rituximab infusion at on-site visits. Clinical improvement was objectively determined by improvement of scale score at least decrease ≥1 INCAT or mRS or increase ≥4 MRC or ≥8 cI-RODS after each infusion compared to baseline evaluation. RESULTS: Fifteen CIDP patients were included and 10 of them were typical CIDP and five were distal CIDP. Nine in 15 (60%) patients after first infusion and three in six (50%) patients after second infusion exhibited significant clinical improvement compared to baseline evaluation. Additionally, rituximab facilitated a reduction or cessation of other medications in 73% of patients at last visit. The safety profile was favorable, with no reported adverse events. CONCLUSION: Rituximab presents a promising therapeutic option for idiopathic CIDP, offering both efficacy and safety with a low-dose, long-term regimen.

Renal Protective Effect of Boeravinone B against Diabetic Nephropathy Rats via Inhibition of The Inflammatory and JAK2/STAT3 Signalling Pathway.

OBJECTIVE: Chronic inflammation is a common feature in diabetes, especially when blood sugar levels are poorly controlled. This chronic low-grade inflammation can affect various organs, including the kidneys. Podocyte damage play a key role in the development of diabetic nephropathy (DN). The aim of the study was to evaluate the nephroprotective effect of Boeravinone B (BB) against streptozotocin (STZ) induced DN in rats and explore the underlying mechanism. MATERIALS AND METHODS: In this experimental study, the rats received intraperitoneal injections of STZ (60 mg/kg) to induce DN. Various doses of BB (2.5, 5, and 7.5 mg/kg) were administered orally. Glucose levels, body weights, and organ weights (hepatic and renal) were assessed. Renal, histomorphological, antioxidant, hepatic, and cytokine levels were determined, as were the mRNA expression levels of JAK2 and STAT3. At end of the experimental study, the rats were sacrificed and their renal tissues were removed for histopathological assessment. RESULTS: BB treatment decreased glucose levels and increased body weights. This treatment suppressed hepatic weights, increased renal tissue weights, and also decreased renal parameters like uric acid, urea, bilirubin, creatinine (Cr) and, albumin. There was a decrease (P<0.001) in histomorphological parameters such as kidney hypertrophy index (KHI), mean glomerular volume (MGV), foot process fusion ratio (FPFR), and glomerular basement membrane thickness (GBMT) after treatment with BB. In addition, this treatment improved the levels of renal podocin, renal CD2- associated protein (CD2AP) and suppressed hepatic parameter levels. BB treatment (P<0.001) altered antioxidant parameters and cytokine levels, and suppressed mRNA expressions of JAK2, STAT3, RAGE, KIM-1, NAGL, and S100A8. CONCLUSION: Administration of BB showed renal protective effects against STZ-induced DN in rats via the reduction of oxidative stress and inflammatory reactions.

The impact of a lung-protective ventilation mode using transpulmonary driving pressure titrated positive end-expiratory pressure on the prognosis of patients with acute respiratory distress syndrome.

OBJECTIVE: This study aimed to assess the impact of a lung-protective ventilation strategy utilizing transpulmonary driving pressure titrated positive end-expiratory pressure (PEEP) on the prognosis [mechanical ventilation duration, hospital stay, 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP), survival outcome] of patients with Acute Respiratory Distress Syndrome (ARDS). METHODS: A total of 105 ARDS patients were randomly assigned to either the control group (n = 51) or the study group (n = 53). The control group received PEEP titration based on tidal volume [A tidal volume of 6 mL/kg, flow rate of 30-60 L/min, frequency of 16-20 breaths/min, constant flow rate, inspiratory-to-expiratory ratio of 1:1 to 1:1.5, and a plateau pressure ≤ 30-35 cmH2O. PEEP was adjusted to maintain oxygen saturation (SaO2) at or above 90%, taking into account blood pressure], while the study group received PEEP titration based on transpulmonary driving pressure (Esophageal pressure was measured as a surrogate for pleural pressure using an esophageal pressure measurement catheter connected to the ventilator. Tidal volume and PEEP were adjusted based on the observed end-inspiratory and end-expiratory transpulmonary pressures, aiming to maintain a transpulmonary driving pressure below 15 cmH2O during mechanical ventilation. Adjustments were made 2-4 times per day). Statistical analysis and comparison were conducted on lung function indicators [oxygenation index (OI), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2)] as well as other measures such as heart rate, mean arterial pressure, and central venous pressure in two groups of patients after 48 h of mechanical ventilation. The 28-day mortality rate, duration of mechanical ventilation, length of hospital stay, and ventilator-associated pneumonia (VAP) incidence were compared between the two groups. A 60-day follow-up was performed to record the survival status of the patients. RESULTS: In the control group, the mean age was (55.55 ± 10.51) years, with 33 females and 18 males. The pre-ICU hospital stay was (32.56 ± 9.89) hours. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was (19.08 ± 4.67), and the mean Murray Acute Lung Injury score was (4.31 ± 0.94). In the study group, the mean age was (57.33 ± 12.21) years, with 29 females and 25 males. The pre-ICU hospital stay was (33.42 ± 10.75) hours. The mean APACHE II score was (20.23 ± 5.00), and the mean Murray Acute Lung Injury score was (4.45 ± 0.88). They presented a homogeneous profile (all P > 0.05). Following intervention, significant improvements were observed in PaO2 and OI compared to pre-intervention values. The study group exhibited significantly higher PaO2 and OI compared to the control group, with statistically significant differences (all P < 0.05). After intervention, the study group exhibited a significant increase in PaCO2 (43.69 ± 6.71 mmHg) compared to pre-intervention levels (34.19 ± 5.39 mmHg). The study group's PaCO2 was higher than the control group (42.15 ± 7.25 mmHg), but the difference was not statistically significant (P > 0.05). There were no significant differences in hemodynamic indicators between the two groups post-intervention (all P > 0.05). The study group demonstrated significantly shorter mechanical ventilation duration and hospital stay, while 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP) showed no significant differences. Kaplan-Meier survival analysis revealed a significantly better survival outcome in the study group at the 60-day follow-up (HR = 0.565, 95% CI: 0.320-0.999). CONCLUSION: Lung-protective mechanical ventilation using transpulmonary driving pressure titrated PEEP effectively improves lung function, reduces mechanical ventilation duration and hospital stay, and enhances survival outcomes in patients with ARDS. However, further study is needed to facilitate the wider adoption of this approach.

A High-Throughput Method for Accurate Extraction of Intact Rice Panicle Traits.

Rice panicle traits serve as critical indicators of both yield potential and germplasm resource quality. However, traditional manual measurements of these traits, which typically involve threshing, are not only laborious and time-consuming but also prone to introducing measurement errors. This study introduces a high-throughput and nondestructive method, termed extraction of panicle traits (EOPT), along with the software Panicle Analyzer, which is designed to assess unshaped intact rice panicle traits, including the panicle grain number, grain length, grain width, and panicle length. To address the challenge of grain occlusion within an intact panicle, we define a panicle morphology index to quantify the occlusion levels among the rice grains within the panicle. By calibrating the grain number obtained directly from rice panicle images based on the panicle morphology index, we substantially improve the grain number detection accuracy. For measuring grain length and width, the EOPT selects rice grains using an intersection over union threshold of 0.8 and a confidence threshold of 0.7 during the grain detection process. The mean values of these grains were calculated to represent all the panicle grain lengths and widths. In addition, EOPT extracted the main path of the skeleton of the rice panicle using the Astar algorithm to determine panicle lengths. Validation on a dataset of 1,554 panicle images demonstrated the effectiveness of the proposed method, achieving 93.57% accuracy in panicle grain counting with a mean absolute percentage error of 6.62%. High accuracy rates were also recorded for grain length (96.83%) and panicle length (97.13%). Moreover, the utility of EOPT was confirmed across different years and scenes, both indoors and outdoors. A genome-wide association study was conducted, leveraging the phenotypic traits obtained via EOPT and genotypic data. This study identified single-nucleotide polymorphisms associated with grain length, width, number per panicle, and panicle length, further emphasizing the utility and potential of this method in advancing rice breeding.

Combined physicochemical and transcriptomic analyses reveal the effect of the OsGA20ox1 gene on the starch properties of germinated brown rice.

Genes play a pivotal role in regulating the germination of cereal grains; however, there is limited research on the impact of germination genes on the physicochemical properties of germinated cereal starch. We investigated the effects of the OsGA20ox1 gene on the multiscale structural features and adhesion behavior of germinated brown rice starch. Compared to the knockout lines group, the wild type exhibited a decrease in double-helix content (62.74 %), relative crystallinity (47.39 %), and short-range molecular ordering (2.47 %), accompanied by enhanced erosion on the surface of starch granules. The damage to glycosidic bonds at the double-helix level and the heightened structural amorphization (90.95 %) led to reduced entanglement and interaction among starch molecules, ultimately resulting in reduced characteristic viscosity. Further transcriptomic analysis revealed that OsGA20ox1 could regulate the expression of starch-related enzyme genes in the starch metabolism pathway during germination of brown rice. This study contributes to understanding the role of germination genes in promoting the physicochemical properties of starch in germinated grains, thereby opening up new avenues for the improvement of plant-based starch, and paving the way for further research in this field.

Rapid nanomolar detection of cocaine in biofluids by electrochemical aptamer-based sensor with low-temperature effect for drugged driving screening.

Cocaine is one of the most abused illicit drugs, and its abuse damages the central nervous system and can even lead directly to death. Therefore, the development of simple, rapid and highly sensitive detection methods is crucial for the prevention and control of drug abuse, traffic accidents and crime. In this work, an electrochemical aptamer-based (EAB) sensor based on the low-temperature enhancement effect was developed for the direct determination of cocaine in bio-samples. The signal gain of the sensor at 10 °C was greatly improved compared to room temperature, owing to the improved affinity between the aptamer and the target. Additionally, the electroactive area of the gold electrode used to fabricate the EAB sensor was increased 20 times by a simple electrochemical roughening method. The porous electrode possesses more efficient electron transfer and better antifouling properties after roughening. These improvements enabled the sensor to achieve rapid detection of cocaine in complex bio-samples. The low detection limits (LOD) of cocaine in undiluted urine, 50% serum and 50% saliva were 70 nM, 30 nM and 10 nM, respectively, which are below the concentration threshold in drugged driving screening. The aptasensor was simple to construct and reusable, which offers potential for drugged driving screening in the real world.

Effects of Progressive and Velocity-Based Autoregulatory Resistance Training on Lower-Limb Movement Ability in Taekwondo Athletes.

BACKGROUND: Both autoregulatory progressive resistance exercise (APRE) and velocity-based resistance training (VBRT) utilize real-time monitoring of athlete physical performance to adjust training loads to provide appropriate training stimuli. However, the monitoring and adjustment approaches differ between both methods. This study aimed to compare the effects of APRE and VBRT on the muscle strength, power, and agility of college taekwondo athletes. HYPOTHESIS: Eight weeks of APRE and VBRT will promote similar results to strength gains in regards maximal strength, but VBRT will be superior to APRE in explosive power and agility. STUDY DESIGN: Clinical trial. LEVEL OF EVIDENCE: Level 3. METHODS: Thirty taekwondo athletes were divided randomly into 2 groups (VBRT/APRE), and all participants completed an 8-week APRE/VBRT intervention. Maximum strength, explosive power, and agility performance were assessed during the squat 1-repetition maximum (1RM), countermovement jump (CMJ), drop jump (DJ), kicking strength test (KST), taekwondo-specific agility test (TSAT), and hexagon test (HT). RESULTS: Highly significant time effects (P < 0.01) were observed for squat 1RM, CMJ, and TSAT in both the APRE and VBRT groups. However, there were no significant group-by-time differences for any of the measured outcomes to intergroup (P > 0.05), but APRE had a small effect size (ES) over VBRT for CMJ (ES = 0.48, η2p = 0.06), TSAT (ES = 0.26, η2p = 0.02), and HT (ES = 0.42, η2p = 0.05). CONCLUSION: An 8-week autoregulatory APRE and VBRT can both effectively improve both the maximal strength, explosive power, and agility performance of taekwondo athletes, with APRE exhibiting potential advantages in improving CMJ, TSAT, and HT. CLINICAL RELEVANCE: These results provide important insights into the selection of suitable resistance training programs by professional coaches, taking into account athlete needs, training efficiency, and safety considerations.

Two-Dimensional M-Chalcogene Family with Tunable Superconducting, Topological, and Magnetic Properties.

An interesting question is whether chalcogen atoms can emulate the role of carbon or boron elements stabilized between two transition metal layers, as observed in MXenes or MBenes. Here, we predict a new family of two-dimensional ternary compounds M4XY2 (where M = Pd, Y, Zr, etc.; X = S, Se, Te; and Y = Cl, Br, I), named M-chalcogene. Through first-principles calculations, we reveal diverse physical properties in these compounds, including superconducting, topological, and magnetic characteristics, where the bilayer transition metals play crucial roles. Moreover, the expected helical edge states and superconducting transition temperatures in Pd4SCl2 can be finely tuned by strains. Additionally, the Ti4SCl2 is predicted to be a topological insulator and shows promise as a gas sensor candidate for certain exotic gases. Our findings expand two-dimensional material families and provide promising platforms for diverse physical phenomena with efficient tunability by external stimuli for various applications.

Cold-hot Janus electrochemical aptamer-based sensor for calibration-free determination of biomolecules.

Real-time, high-frequency measurements of pharmaceuticals, metabolites, exogenous antigens, and other biomolecules in biological samples can provide critical information for health management and clinical diagnosis. Electrochemical aptamer-based (EAB) sensor is a promising analytical technique capable of achieving these goals. However, the issues of insufficient sensitivity, frequent calibration and lack of adapted portable electrochemical device limit its practical application in immediate detection. In response we have fabricated an on-chip-integrated, cold-hot Janus EAB (J-EAB) sensor based on the thermoelectric coolers (TECs). Attributed to the Peltier effect, the enhanced/suppressed current response can be generated simultaneously on cold/hot sides of the J-EAB sensor. The ratio of the current responses on the cold and hot sides was used as the detection signal, enabling rapid on-site, calibration-free determination of small molecules (procaine) as well as macromolecules (SARS-CoV-2 spike protein) in single step, with detection limits of 1 µM and 10 nM, respectively. We have further demonstrated that the J-EAB sensor is effective in improving the ease and usability of the actual detection process, and is expected to provide a universal, low-cost, fast and easy potential analytical tool for other clinically important biomarkers, drugs or pharmaceutical small molecules.

SLC2A1 boosts the resistance of non-small cell lung cancer to taxanes by stimulating the formation of EPCAM+ cancer stem-like cells via glycolysis.

BACKGROUND: The mechanisms by which SLC2A1 enhances chemo-resistance of taxanes to non-small cell lung cancer (NSCLC) remains enigmatic. METHODS: An investigation into the SLC2A1 expression pattern and prognosis across diverse datasets, as well as our internally collected samples, was undertaken. Additionally, the biological function of SLC2A1 was further delved into through in vitro experiments. The study also examined the chemo-resistance of NSCLC to taxanes using CCK-8, Annexin-V, and caspase-3 assays. Furthermore, the impact of taxanes on SLC2A1 expression was determined via western blot analysis. The effects of SLC2A1 on the formation of CSCs was examined via flow cytometry and metabolomics techniques. Finally, the impact of SLC2A1 on the tumor microenvironment was analyzed using single-cell sequencing and cellchat. RESULTS: In the present investigation, it was observed that there was an elevated expression of SLC2A1 in NSCLC tumor tissues, which exhibited a significant association with a poorer prognosis. SLC2A1 overexpression in vitro promoted NSCLC cell proliferation, invasion, migration, chemo-resistance, and the formation of CD90+ and EpCAM+ CSCs. NSCLC cells were categorized based on SLC2A1 and EpCAM expression. SLC2A1highEpCAM+ CSCs were more chemo-resistance to taxanes. NSCLC patients with high SLC2A1 and EpCAM expression had poorer prognosis. Mechanically, SLC2A1 promoted the formation of CD90+ and EpCAM+ CSCs via activating glycolysis. Finally, SLC2A1low tumor cells promoted CD8+T cell function via HLA-A, B, C, and suppressed NK cell function via HLA-E. CONCLUSION: Together, SLC2A1 plays an important role in enhancing chemo-resistance of taxanes to NSCLC.

CsMIKC1 regulates inflorescence development and grain production in Cannabis sativa plants.

Female inflorescence is the primary output of medical Cannabis. It contains hundreds of cannabinoids that accumulate in the glandular trichomes. However, little is known about the genetic mechanisms governing Cannabis inflorescence development. In this study, we reported the map-based cloning of a gene determining the number of inflorescences per branch. We named this gene CsMIKC1 since it encodes a transcription factor that belongs to the MIKC-type MADS subfamily. Constitutive overexpression of CsMIKC1 increases inflorescence number per branch, thereby promoting flower production as well as grain yield in transgenic Cannabis plants. We further identified a plant-specific transcription factor, CsBPC2, promoting the expression of CsMIKC1. CsBPC2 mutants and CsMIKC1 mutants were successfully created using the CRISPR-Cas9 system; they exhibited similar inflorescence degeneration and grain reduction. We also validated the interaction of CsMIKC1 with CsVIP3, which suppressed expression of four inflorescence development-related genes in Cannabis. Our findings establish important roles for CsMIKC1 in Cannabis, which could represent a previously unrecognized mechanism of inflorescence development regulated by ethylene.

Identifying Factors Associated with Fast Visual Field Progression in Patients with Ocular Hypertension Based on Unsupervised Machine Learning.

PURPOSE: To identify ocular hypertension (OHT) subtypes with different trends of visual field (VF) progression based on unsupervised machine learning and to discover factors associated with fast VF progression. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: A total of 3133 eyes of 1568 ocular hypertension treatment study (OHTS) participants with at least five follow-up VF tests were included in the study. METHODS: We used a latent class mixed model (LCMM) to identify OHT subtypes using standard automated perimetry (SAP) mean deviation (MD) trajectories. We characterized the subtypes based on demographic, clinical, ocular, and VF factors at the baseline. We then identified factors driving fast VF progression using generalized estimating equation (GEE) and justified findings qualitatively and quantitatively. MAIN OUTCOME MEASURE: Rates of SAP mean deviation (MD) change. RESULTS: The LCMM model discovered four clusters (subtypes) of eyes with different trajectories of MD worsening. The number of eyes in clusters were 794 (25%), 1675 (54%), 531 (17%) and 133 (4%). We labeled the clusters as Improvers (cluster 1), Stables (cluster 2), Slow progressors (cluster 3), and Fast progressors (cluster 4) based on their mean of MD decline rate, which were 0.08, -0.06, -0.21, and -0.45 dB/year, respectively. Eyes with fast VF progression had higher baseline age, intraocular pressure (IOP), pattern standard deviation (PSD) and refractive error (RE), but lower central corneal thickness (CCT). Fast progression was associated with being male, heart disease history, diabetes history, African American race, and stroke history. CONCLUSION: Unsupervised clustering can objectively identify OHT subtypes including those with fast VF worsening without human expert intervention. Fast VF progression was associated with higher history of stroke, heart disease and diabetes. Fast progressors were more from African American race , males and had higher incidence of glaucoma conversion. Subtyping can provide guidance for adjusting treatment plans to slow vision loss and improve quality of life of patients with a faster progression course.

MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression.

BACKGROUND: The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. METHODS: In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. RESULTS: Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79-87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. CONCLUSIONS: Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Treating chronic atrophic gastritis: identifying sub-population based on real-world TCM electronic medical records.

Background and Objective: Chronic atrophic gastritis (CAG) is a complex chronic disease caused by multiple factors that frequently occurs disease in the clinic. The worldwide prevalence of CAG is high. Interestingly, clinical CAG patients often present with a variety of symptom phenotypes, which makes it more difficult for clinicians to treat. Therefore, there is an urgent need to improve our understanding of the complexity of the clinical CAG population, obtain more accurate disease subtypes, and explore the relationship between clinical symptoms and medication. Therefore, based on the integrated platform of complex networks and clinical research, we classified the collected patients with CAG according to their different clinical characteristics and conducted correlation analysis on the classification results to identify more accurate disease subtypes to aid in personalized clinical treatment. Method: Traditional Chinese medicine (TCM) offers an empirical understanding of the clinical subtypes of complicated disorders since TCM therapy is tailored to the patient's symptom profile. We gathered 6,253 TCM clinical electronic medical records (EMRs) from CAG patients and manually annotated, extracted, and preprocessed the data. A shared symptom-patient similarity network (PSN) was created. CAG patient subgroups were established, and their clinical features were determined through enrichment analysis employing community identification methods. Different clinical features of relevant subgroups were correlated based on effectiveness to identify symptom-botanical botanical drugs correspondence. Moreover, network pharmacology was employed to identify possible biological relationships between screened symptoms and medications and to identify various clinical and molecular aspects of the key subtypes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: 5,132 patients were included in the study: 2,699 males (52.60%) and 2,433 females (47.41%). The population was divided into 176 modules. We selected the first 3 modules (M29, M3, and M0) to illustrate the characteristic phenotypes and genotypes of CAG disease subtypes. The M29 subgroup was characterized by gastric fullness disease and internal syndrome of turbidity and poison. The M3 subgroup was characterized by epigastric pain and disharmony between the liver and stomach. The M0 subgroup was characterized by epigastric pain and dampness-heat syndrome. In symptom analysis, The top symptoms for symptom improvement in all three subgroups were stomach pain, bloating, insomnia, poor appetite, and heartburn. However, the three groups were different. The M29 subgroup was more likely to have stomach distention, anorexia, and palpitations. Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon were the most popular botanical drugs. The M3 subgroup has a higher incidence of yellow urine, a bitter tongue, and stomachaches. Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora were the botanical drugs used. Vomiting, nausea, stomach pain, and appetite loss are common in the M0 subgroup. The primary medications are Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia. Through GO and KEGG pathway analysis, We found that in the M29 subgroup, Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon may exert their therapeutic effects on the symptoms of gastric distension, anorexia, and palpitations by modulating apoptosis and NF-κB signaling pathways. In the M3 subgroup, Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora may be treated by NF-κB and JAK-STAT signaling pathway for the treatment of stomach pain, bitter mouth, and yellow urine. In the M0 subgroup, Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia may exert their therapeutic effects on poor appetite, stomach pain, vomiting, and nausea through the PI3K-Akt signaling pathway. Conclusion: Based on PSN identification and community detection analysis, CAG population division can provide useful recommendations for clinical CAG treatment. This method is useful for CAG illness classification and genotyping investigations and can be used for other complicated chronic diseases.

Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Characteristics and treatment of a silent somatotroph tumor that had transformed to a functional type: a case report and literature review.

Background: "Functionalization" of silent pituitary neuroendocrine tumors (PitNETs) is a pretty rare clinical phenomenon that reportedly occurs most often with silent corticotroph tumors (SCTs). We report the case of silent somatotroph tumor (SST) that had transformed to functional type. We also review similar cases of SST with functionalization. Case Description: A 43-year-old man without suggestive symptoms of a pituitary tumor was referred with a lesion in the sellar region detected incidentally. Serum insulin-like growth factor 1 (IGF-1) (348 ng/mL) was high, whereas growth hormone (GH) was within the normal range. A glucose GH inhibition test showed inhibition of GH to 0.4 ng/mL. Subtotal tumorectomy was performed via a transnasal-sphenoidal approach. Histopathological examination of the operative specimen showed weak expression of GH and diffuse staining of pituitary-specific transcription factor-1 (Pit-1). The final pathological diagnosis was SST. Five years after the first surgery without follow-up, the patient presented again because of headache, impaired vision, bone pain, and high blood glucose concentrations for 2 months. Physical examination showed early acromegalic features. Of interest, greatly increased concentrations of GH (7.2 ng/mL) and IGF-1 (533 ng/mL) were found. Magnetic resonance imaging showed the recurrence of tumor. A diagnosis of acromegaly was considered. The patient underwent a second transsphenoidal pituitary tumor resection, after which his serum GH and IGF-1 concentrations decreased. Unlike the original surgical specimen, immunohistochemical examination of the tissue resected during the second surgery showed strong GH positivity, with similarly strong Pit-1 positivity. The patient was followed up for 6 months without octreotide treatment. At the last follow-up, he was found to have high serum concentrations of GH and IGF-1, which demonstrated another progression of the remnant PitNET. After two courses of octreotide acetate microspheres (20 mg/month), the acromegaly was under control. Conclusions: In addition to SCTs, other silent PitNETs could also functionalize. Medical teams of PitNETs should recognize this rare phenomenon and conduct long-term follow-up. After functionalization, these tumors have a high recurrence rate, requiring multiple therapies and long-term follow-up. Further research is essential to determine the mechanism of regulation of secretion of GH by such tumors.