Transepithelial transport of nanoparticles in oral drug delivery: From the perspective of surface and holistic property modulation.

Despite the promising prospects of nanoparticles in oral drug delivery, the process of oral administration involves a complex transportation pathway that includes cellular uptake, intracellular trafficking, and exocytosis by intestinal epithelial cells, which are necessary steps for nanoparticles to enter the bloodstream and exert therapeutic effects. Current researchers have identified several crucial factors that regulate the interaction between nanoparticles and intestinal epithelial cells, including surface properties such as ligand modification, surface charge, hydrophilicity/hydrophobicity, intestinal protein corona formation, as well as holistic properties like particle size, shape, and rigidity. Understanding these properties is essential for enhancing transepithelial transport efficiency and designing effective oral drug delivery systems. Therefore, this review provides a comprehensive overview of the surface and holistic properties that influence the transepithelial transport of nanoparticles, elucidating the underlying principles governing their impact on transepithelial transport. The review also outlines the chosen of parameters to be considered for the subsequent design of oral drug delivery systems.

Stratified analysis of the association between anti-obesity medications and digestive adverse events: a real-world study based on the FDA adverse event reporting system database.

BACKGROUND: Numerous digestive system adverse events (dsAEs) have been observed during the use of anti-obesity medications (AOMs), leading to concerns about the safety of these medications. However, most current studies are limited to the association of one class of drugs with specific digestive disorders, and there is no cascading analysis of AOMs in the digestive system. This study aims to use data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) for a stratified analysis of the reported associations between AOMs and dsAEs. METHODS: We analyzed adverse event reports submitted to FAERS between January 2015 and December 2023 related to obesity treatment. It is important to note that FAERS data cannot establish causality or incidence rates. Pharmacovigilance (PV) signals were detected by disproportionate analyses through proportionate reporting ratio (PRR), reporting odds ratios (ROR), and information components (IC) to detect dsAEs associated with AOMs. Reporting rates, severity, and response outcomes of digestive adverse events were compared across AOMs by multivariate logistic regression analysis. RESULTS: Among 34,396 adverse events (AEs) related to obesity treatment, 8844 dsAEs were analyzed. Comparing with semaglutide and liraglutide, tirzepatide exhibited fewer reported dsAEs while semaglutide and liraglutide showed a high correlation with non-lethal pancreatitis reports. Bupropion-naltrexone (31.65%) reported the highest number of dsAEs, and a PV signal was detected in mouth and lips AEs (ROR = 2.97, 95% CI: 2.42-3.6). Orlistat (ROR = 3.30, 95% CI: 3.08-3.55) exhibited the highest association with gastrointestinal AEs compared to other AOMs. PV signal for hepatobiliary AEs (ROR = 6.13, 95% CI: 3.45-10.88) with phentermine-topiramate still needs further clarification. CONCLUSIONS: Tirzepatide may be considered for patients with a history of digestive system disease or an elevated risk of pancreatitis based on the pattern of reported dsAEs. Caution is needed for the orofacial AEs when using bupropion-naltrexone. Orlistat has a higher reporting rate of gastrointestinal AEs, but these events are typically less severe. Phentermine-topiramate's association with liver impairment requires further clinical investigation. This article provides insights into the reported associations between AOMs and dsAEs, which may aid clinicians in making more informed decisions about individualizing medication and managing potential adverse events.

Robust, superabsorbent and antibacterial polysaccharide-based hybrid-network hydrogels for wound repair.

Hydrogel dressings with multiple functions are ideal options for wound repair. This study developed hydrogel dressings by interpenetrating the physically crosslinked xanthan gum (XG)/carboxylated chitosan (CCS) network and the chemically crosslinked polyacrylamide (PAAm) network via a one-pot method. The XG-CCS/PAAm hydrogels were found to display tunable mechanical properties, due to the formation of strong network structure. The hydrogels exhibited the strongest tensile strength of 0.6 MPa at an XG/CCS ratio of 40/60, while the largest compressive strength of 4.5 MPa is achieved at an XG/CCS ratio of 60/40. Moreover, the hydrogel with an XG/CCS ratio of 60/40 exhibited desirable adhesion strength on porcine skin, which was 3.7 kPa. It also had a swelling ratio, as high as 1200 %. After loading with cephalexin, the XG-CCS/PAAm hydrogels can deliver the antibacterial drugs following a first-order kinetic. As a result, both E. coli and S. aureus can be completely inactivated by the cefalexin-loaded hydrogels after 12 h. Furthermore, the XG-CCS/PAAm hydrogels were found to exhibit excellent biocompatibility as well as effective wound healing ability, as proven by the in vitro and in vivo tests. In this regard, XG-CCS/PAAm hydrogels can act as promising multifunctional wound dressings.

Physiologically-based pharmacokinetic/pharmacodynamic modeling of meropenem in critically ill patients.

This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients. A PBPK model of meropenem in healthy adults was established using PK-Sim software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0-∞, and CL to evaluate the accuracy of the PBPK model. The model was verified using meropenem plasma samples obtained from Intensive Care Unit (ICU) patients, which were determined by HPLC-MS/MS. After that, the PBPK model was combined with a PKPD model, which was developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients. The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within the 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted with 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that meropenem PBPK modeling is well simulated in critically ill patients. Monte Carlo simulations showed that extended infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4 h) was unnecessary. The PBPK/PD modeling incorporating literature and prospective study data can predict meropenem pharmacokinetics in critically ill patients correctly. Our study provides a reference for dose adjustment in critically ill patients.

Visible Light-sensitized CO2 Methanation along a Relaxed Heat Available Route.

In photocatalysis, the resulted heat by the relaxation of most of incident light no longer acts as the industrially favorite driving force back to the target photo-reaction due to more or less the negative relation between photocatalytic efficiency and temperature. Here, we reported a visible light-sensitized protocol that completely reversed the negatively temperature-dependent efficiency in photo-driven CO2 methanation with saturated water vapor. Uniform Pt/N-TiO2/PDI self-assembly material decisively injects the excited electron of PDI sensitizer into N-TiO2 forming Ti-H hydride which is crucially temperature-dependent nucleophilic species to dominate CO2 methanation, rather than conventionally separated and trapped electrons on the conductor band. Meanwhile, the ternary composite lifts itself temperature from room temperature to 305.2 °C within 400s only by the failure excitation upon simulated sunlight of 2.5 W/cm2, and smoothly achieves CO2 methanation with a record number of 4.98 mmol g-1 h-1 rate, compared to less than 0.02 mmol g-1 h-1 at classic Pt/N-TiO2/UV photocatalysis without PDI sensitization. This approach can reuse ~53.9% of the relaxed heat energy from the incident light thereby allow high-intensity incident light as strong as possible within a flowing photo-reactor, opening the most likely gateways to industrialization.

A Novel Automated Aspiration of Subretinal Fluid Method During Scleral Buckling For Rhegmatogenous Retinal Detachment.

PURPOSE: The goal of the study is to introduce a modified technique for the removal of subretinal fluid during scntleral buckling (SB) to treat rhegmatogenous retinal detachment (RRD). METHODS: This case series study was comprised of 18 cases of RRD patients suffering from a novel automated aspiration of subretinal fluid method during SB. The cases took place from July 2023 to November 2023 at the First Affiliated Hospital of USTC. Preoperative and intraoperative situations were evaluated, and spectral-domain optical coherence (SDOCT) and scanning laser ophthalmoscopy were used to observe the absorption of SRF in the early postoperative period. RESULTS: The SRF method's automated aspiration primarily eliminated the SRF of all 18 RRD cases during SB surgery, leading to retinal reattachment, as showed by SLO. The method did not cause extensive intraoperative hemorrhage and had no risk of retinal incarceration or other complications. The SDOCT showed that the height of SRF in the macular area decreased in 10 cases (66.67%), leaving just a thin layer; was completely cleared in two cases (13.33%); had just a macular single bleb in one case (6.67%); and had several blebs left in two cases (13.33%). CONCLUSIONS: These findings suggest that the automated aspiration of the SRF method is effective, controllable, and beneficial for retinal reattachment, especially in the early postoperative period. Complications with this method were rare.

CMTM5 influences Hippo/YAP axis to promote ferroptosis in glioma through regulating WWP2-mediated LATS2 ubiquitination.

Glioma, a common malignancy, is characterized by high morbidity and mortality. Promoting ferroptosis can delay tumor progression. Here, we aimed to explore the underlying mechanism of ferroptosis in glioma. In vitro and in vivo experiments were conducted using glioma cells and nude mice. The expression of genes and proteins was evaluated by RT-qPCR, Western blot assay, and immunohistochemical staining. Malignant activities of glioma cells were evaluated using MTT, EdU, and Transwell assays. The levels of Fe2+, lipid reactive oxygen species, and malondialdehyde were determined using commercial kits. The interplays among CMTM5, WWP2, and LATS2 were validated using Co-immunoprecipitation assay. The UALCAN database predicted downregulation of CMTM5 expression in glioma, and low expression of CMTM5 was associated with poor survival outcomes. CMTM5 overexpression inhibited cell growth and invasion and promoted ferroptosis of glioma cells. Besides, CMTM5 protein interacted with WWP2 protein and decreased WWP2 expression. WWP2 silencing attenuated LATS2 ubiquitination to enhance LATS2 expression and phosphorylation of YAP1. CMTM5 exerted a suppressive effect on cell growth and invasion and promoted ferroptosis of glioma cells by regulating the WWP2/LATS2 pathway. In the in vivo experiments, CMTM5 overexpression suppressed tumor growth and enhanced ferroptosis. CMTM5 regulated Hippo/YAP signaling to inhibit cell growth and invasion and to promote ferroptosis in glioma by regulating WWP2-mediated LATS2 ubiquitination, thereby attenuating glioma progression.

Comparison of Infection Risks Between Various Inhaled and Intranasal Corticosteroids: A Pharmacovigilance Analysis Based on the FAERS Database.

Purpose: This study conducted a pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) database to compare the infection risk of inhaled or nasal Beclomethasone, Fluticasone, Budesonide, Ciclesonide, Mometasone, and Triamcinolone Acetonide. Methods: We used proportional imbalance analysis to evaluate the correlation between ICS /INCs and infection events. The data was extracted from the FAERS database from April 2015 to September 2023. Further analysis was conducted on the clinical characteristics, site of infection, and pathogenic bacteria of ICS and INCs infection adverse events (AEs). We used bubble charts to display their top 5 infection adverse events. Results: We analyzed 21,837 reports of infection AEs related to ICS and INCs, with an average age of 62.12 years. Among them, 61.14% of infection reports were related to females. One-third of infections reported to occur in the lower respiratory tract with Fluticasone, Budesonide, Ciclesonidec, and Mometasone; over 40% of infections reported by Triamcinolone Acetonide were eye infections; the rate of oral infections caused by Beclomethasone were 7.39%. The reported rates of fungal and viral infections caused by beclomethasone were 21.15% and 19.2%, respectively. The mycobacterial infections caused by Budesonide and Ciclesonidec account for 3.29% and 2.03%, respectively. Bubble plots showed that the ICS group had more fungal infections, oral infections, pneumonia, tracheitis, etc. The INCs group had more eye symptoms, rhinitis, sinusitis, nasopharyngitis, etc. Conclusion: Women who use ICS and INCs are more prone to infection events. Compared to Budesonide, Fluticasone seemed to have a higher risk of pneumonia and oral candidiasis. Mometasone might lead to more upper respiratory tract infections. The risk of oral infection was higher with Beclomethasone. Beclomethasone causes more fungal and viral infections, while Ciclesonide and Budesonide are more susceptible to mycobacterial infections.

Impact of HIV-1 genetic diversity on disease progression: a prospective cohort study in Guangxi.

The high proportion of AIDS cases and mortality rates in Guangxi underscores the urgency to investigate the influence of HIV-1 genetic diversity on disease progression in this region. Newly diagnosed HIV-1 patients were enrolled from January 2016 to December 2021, and the follow-up work and detection of CD4+T lymphocytes were carried out every six months until December 2022. Multivariate logistic regression was used to analyze the factors affecting pre-treatment CD4+T lymphocyte counts, while local weighted regression models (LOESS) and generalized estimating equation models (GEE) were conducted to assess factors influencing CD4+T Lymphocyte Recovery. Cox regression analysis was utilized to examine the impact of subtypes on survival risk. Additionally, HIV-1 env sequences were utilized for predicting CXCR4 and CCR5 receptors. The study encompassed 1867 individuals with pol sequences and 281 with env sequences. Our findings indicate that age over 30, divorced/widowed, peasant, heterosexual infection, CRF01_AE, long-term infection, and Pre-treatment Viral load >10000 copies/ml were factors associated with higher risk for pre-treatment CD4+T lymphocyte decline. Specifically, male gender, age over 30, heterosexual infection (HETs), long-term infection, CRF01_AE, and Pre-treatment CD4 T cell counts below 350/µL were identified as risk factors impeding CD4+T lymphocyte recovery. Pre-treatment CD4+T lymphocyte counts and recovery in individuals infected with CRF01_AE were lower compared to CRF07_BC and CRF55_01B. Additionally, CRF01_AE and CRF08_BC subtypes exhibited higher mortality rates than CRF07_BC, CRF55_01B, and other subtypes. Notably, CRF01_AE demonstrated the highest percentage of CXCR4 affinity ratios. This research unveils the intricate influence of HIV-1 gene diversity on CD4+T lymphocyte dynamics and clinical outcomes. It highlights the multifaceted nature of HIV infection in Guangxi, providing novel insights into subtype-specific disease progression among HIV-infected individuals in this region.

Reciprocal Interaction with Neutrophils Facilitates Cutaneous Accumulation of Liposomes.

Liposomes are versatile drug delivery systems in clinical use for cancer and many other diseases. Unfortunately, PEGylated liposomal doxorubicin (sLip/DOX) exhibits serious dose-limiting cutaneous toxicities, which are closely related to the extravascular accumulation of sLip/DOX in the dermis. No clinical interventions have been proposed for cutaneous toxicities due to the elusive transport pathways. Herein, we showed that the reciprocal interaction between liposomes and neutrophils played pivotal roles in liposome extravasation into the dermis. Neutrophils captured liposomes via the complement receptor 3 (CD11b/CD18) recognizing the fragment of complement component C3 (iC3b) deposited on the liposomal surface. Uptake of liposomes also activated neutrophils to induce CD11b upregulation and enhanced the ability of neutrophils to migrate outside the capillaries. Furthermore, inhibition of complement activation either by CRIg-L-FH (a C3b/iC3b targeted complement inhibitor) or blocking the phosphate negative charge in mPEG-DSPE could significantly reduce liposome uptake by neutrophils and alleviate the cutaneous accumulation of liposomes. These results validated the liposome extravasation pathway mediated by neutrophils and provided potential solutions to the devastating cutaneous toxicities occurring during sLip/DOX treatment.

Impact of dairy supplementation on bone acquisition in children's limbs: a 12-month cluster-randomized controlled trial and meta-analysis.

The impact of milk on bone health in rural preschoolers is under-researched. This study, through a clinical trial and a meta-analysis, finds that milk supplementation enhances forearm and calcaneus bone acquisition in children, supporting the benefits of daily milk consumption. PURPOSE: This study evaluated the impact of dairy supplementation on bone acquisition in children's limbs through a cluster-randomized controlled trial and a meta-analysis. METHODS: The trial involved 315 children (4-6 year) from Northwest China, randomized to receive either 390 ml of milk daily (n = 215) or 20-30 g of bread (n = 100) over 12 months. We primarily assessed bone mineral density (BMD) and content (BMC) changes at the limbs, alongside bone-related biomarkers, measured at baseline, the 6th and 12th months. The meta-analysis aggregated BMD or BMC changes in the forearm/legs/calcaneus from published randomized trials involving children aged 3-18 years supplemented with dairy foods (vs. control group). RESULTS: Of 278 completed the trial, intention-to-treat analysis revealed significant increases in BMD (4.05% and 7.31%) and BMC (4.69% and 7.34%) in the left forearm at the 6th and 12th months in the milk group compared to controls (P < 0.001). The calcaneus showed notable improvements in BMD (2.01%) and BMC (1.87%) at 6 months but not at 12 months. Additionally, milk supplementation was associated with beneficial changes in bone resorption markers, parathyroid hormone (- 12.70%), insulin-like growth factor 1 (6.69%), and the calcium-to-phosphorus ratio (2.22%) (all P < 0.05). The meta-analysis, encompassing 894 children, indicated that dairy supplementation significantly increased BMD (SMD, 0.629; 95%CI: 0.275, 0.983) and BMC (SMD, 0.616; 95%CI: 0.380, 0.851) (P < 0.05) in the arms, but not in the legs (P > 0.05). CONCLUSION: Milk supplementation significantly improves bone health in children's forearms, underscoring its potential as a strategic dietary intervention for bone development. Trial registration NCT05074836.

Tirbanibulin decreases cell proliferation and downregulates protein expression of oncogenic pathways in human papillomavirus containing HeLa cells.

Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 ( +) squamous cell carcinoma (SCC), HPV-16 ( +) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against the Src canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half-maximal inhibitory concentration (IC50) of HeLa cells to be 31.49 nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src (p < 0.001), phospho-Src (p < 0.001), Ras (p < 0.01), c-Raf (p < 0.001), ERK1 (p < 0.001), phospho-ERK1 (p < 0.001), phospho-ERK2 (p < 0.01), phospho-Mnk1 (p < 0.001), eIF4E (p < 0.01), phospho-eIF4E (p < 0.001), E6 (p < 0.01), E7 (p < 0.01), Rb (p < 0.01), phospho-Rb (p < 0.001), MDM2 (p < 0.01), E2F1 (p < 0.001), phospho-FAK (p < 0.001), phospho-p130 Cas (p < 0.001), Mcl-1 (p < 0.01), and Bcl-2 (p < 0.001), but upregulates cPARP (p < 0.001), and cPARP/fPARP (p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.

Tirbanibulin is Promising Novel Therapy for Human Papillomavirus (HPV)-associated Diseases.Tirbanibulin 1% ointment is an approved synthetic topical ointment for treating actinic keratoses (AK), a precancer of skin cancer. Topical tirbanibulin has previously been reported to clinically resolve human papillomavirus (HPV)-( +) diseases.In this study, we examine how tirbanibulin may affect the HPV and pathways associated with cancer.We treated the HeLa cell line to determine the effects on HPV cell proliferation. Increasing the concentration of tirbanibulin statistically significantly affected numerous cellular pathways often associated with cancer.These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins and thereby kill cancer cells.

Urban-rural disparities in the short-term effects of cold and heat on myocardial infarction mortality in Anhui Province, China.

Non-optimal ambient temperatures are risk factors for myocardial infarction (MI) and urban-rural temperature differences in the context of climate change may have caused and will lead to differential association between temperature and MI. We collected daily mean temperature and daily MI deaths from 1 January 2016 to 31 December 2020 in Anhui Province, China. A distributed lag nonlinear model was performed to estimate the area-specific association of heat and cold (defined as the 2.5th and 97.5th percentile of the daily mean temperature) with MI mortality; the random-effects meta-analysis was then used to pool the effects of cold and heat. We found the risk of MI death due to cold was higher in rural areas [relative risk (RR): 1.13, 95% confidence interval (CI): 1.02-1.26, lag0) than in urban areas (RR: 0.99, 95% CI: 0.80-1.21, lag0), whereas the risk of MI death associated with heat was higher in urban areas (RR: 1.14, 95% CI: 1.03-1.27, lag0) than in rural areas (RR: 1.04, 95% CI: 0.99-1.10, lag0). Our findings may help to develop targeted protective strategies to reduce the adverse effects of cold and heat on cardiovascular disease.

Exploring the therapeutic mechanisms of Coptidis Rhizoma in gastric precancerous lesions: a network pharmacology approach.

BACKGROUND: Gastric precancerous lesions are a critical stage in the development of gastric cancer or gastric adenocarcinoma, and their outcome plays an important role in the malignant progression of gastric cancer. Coptidis Rhizoma has a good effect on Gastric precancerous lesions. However, the specific mechanisms of its action remain incompletely elucidated. METHODS: Network pharmacology and molecular docking techniques were used to explore the active ingredients and molecular mechanism of Coptidis Rhizoma in treating gastric precancerous lesions. The active compounds of Coptidis Rhizoma and their potential gastric precancerous lesions related targets were obtained from TCMSP, GeneCards, and OMIM databases. An interaction network based on protein-protein interactions (PPIs) was constructed to visualize the interactions between hub genes. Analysis of GO enrichment and KEGG pathway were conducted using the DAVID database. An investigation of interactions between active compounds and potential targets was carried out by molecular docking. Finally, animal experiments were conducted to verify the effect and mechanism of Coptidis Rhizoma in treating precancerous lesions of gastric cancer. RESULTS: A total of 11 active compounds and 95 anti-gastric precancerous lesions targets of Coptidis Rhizoma were screened for analysis. GO enrichment analysis showed that the mechanism of Coptidis Rhizoma acting on gastric precancerous lesions involves gene expression regulation and apoptosis regulation. KEGG pathway enrichment analysis showed that Coptidis Rhizoma against gastric precancerous lesions involving the AKT /HIF-1α/VEGF signalling pathway. Molecular docking simulations indicated potential interactions between these compounds and core targets involved in anti-gastric precancerous lesions activity. In addition, it was confirmed in vivo that Berberine and Coptidis Rhizoma may reverse atrophy and potential intestinal metaplasia by inhibiting the expression of p-AKT, HIFA, and VEGF. CONCLUSION: Bioactive compounds in Coptidis Rhizoma have the potential to prevent atrophy and intestinal metaplasia. These compounds function by regulating the proteins implicated in AKT /HIF-1α/VEGF signalling pathways that are crucial in gastric epithelial cell differentiation, proliferation and maturation.

The effect of selinexor on prostaglandin synthesis in virus-positive Merkel cell carcinoma cell lines.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.

Genome-wide identification of starch phosphorylase gene family in Rosa chinensis and expression in response to abiotic stress.

Chinese rose (Rosa chinensis) is an important ornamental plant, with economic, cultural, and symbolic significance. During the application of outdoor greening, adverse environments such as high temperature and drought are often encountered, which affect its application scope and ornamental quality. The starch phosphorylase (Pho) gene family participate in the synthesis and decomposition of starch, not only related to plant energy metabolism, but also plays an important role in plant stress resistance. The role of Pho in combating salinity and high temperature stress in R. chinensis remains unknown. In this work, 4 Phos from R. chinensis were detected with Pfam number of Pho (PF00343.23) and predicted by homolog-based prediction (HBP). The Phos are characterized by sequence lengths of 821 to 997 bp, and the proteins are predicted to subcellularly located in the plastid and cytoplasm. The regulatory regions of the Phos contain abundant stress and phytohormone-responsive cis-acting elements. Based on transcriptome analysis, the Phos were found to respond to abiotic stress factors such as drought, salinity, high temperature, and plant phytohormone of jasmonic acid and salicylic acid. The response of Phos to abiotic stress factors such as salinity and high temperature was confirmed by qRT-PCR analysis. To evaluate the genetic characteristics of Phos, a total of 69 Phos from 17 species were analyzed and then classified into 3 groups in phylogenetic tree. The collinearity analysis of Phos in R. chinensis and other species was conducted for the first time. This work provides a view of evolution for the Pho gene family and indicates that Phos play an important role in abiotic stress response of R. chinensis.

Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling.

Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to ß-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.

Clinical outcomes of serial endoscopic balloon dilation for duodenal Crohn's disease-associated strictures.

BACKGROUND: Endoscopic balloon dilation (EBD) is a safe and effective treatment for Crohn's disease (CD)-associated strictures. However, serial EBDs have rarely been reported. This study aimed to evaluate the efficacy and safety of serial EBDs for treating CD-associated duodenal strictures compared with intermittent EBDs. METHODS: Patients with CD-associated duodenal strictures who underwent EBD were recruited. The clinical data, stricture characteristics, number of EBDs, dilation diameter, complications, surgical interventions, and follow-up periods were recorded. Patients were divided into a serial dilation group and an intermittent dilation group to analyze the differences in safety and efficacy. RESULTS: Forty-five patients with duodenal CD-associated strictures underwent a total of 139 dilations. A total of 23 patients in the serial dilation group underwent 72 dilations, for a median of 3 (range 3 ~ 4) dilations per patient, and 22 patients in the intermittent dilation group underwent 67 dilations, for a median of 3 (range 1 ~ 6) dilations per patient. Technical success was achieved in 97.84% (136/139) of the patients. During the follow-up period, three patients in the intermittent dilation group underwent surgery, and the total clinical efficacy was 93.33% (42/45). No difference in safety or short-term efficacy was noted between the two groups, but serial EBDs exhibited significantly greater clinical efficacy between 6 months and 2 years. No significant difference in recurrence-free survival was observed, but the median longest recurrence-free survival and recurrence-free survival after the last EBD in the serial dilation group were 693 days (range 298 ~ 1381) and 815 days (range 502 ~ 1235), respectively, which were significantly longer than the 415 days (range 35 ~ 1493) and 291 days (range 34 ~ 1493) in the intermittent dilation group (p = 0.013 and p = 0.000, respectively). At the last follow-up, the mean diameter of the duodenal lumen was 1.17 ± 0.07 cm in the serial dilation group, which was greater than the 1.11 ± 0.10 cm in the intermittent dilation group (p = 0.018). We also found that the Simple Endoscopic Score for Crohn's Disease was associated with an increased risk of surgical intervention (HR 2.377, 95% CI 1.125-5.020; p = 0.023) and recurrence at 6 months after the last EBD (HR 0.698, 95% CI 0.511-0.953; p = 0.024), as assessed by univariate analysis. CONCLUSIONS: Compared to the intermittent EBDs, serial EBDs for duodenal CD-associated strictures exhibit greater clinical efficacy within two years and could delay stricture recurrence. We suggest that serial EBDs can be a novel option for endoscopic treatment of duodenal CD-associated strictures.

Exogenous Indole-3-Acetic Acid Suppresses Rice Infection of Magnaporthe oryzae by Affecting Plant Resistance and Fungal Growth.

Auxin is an important phytohormone that regulates diverse biologic processes, including plant growth and immunity. Indole-3-acetic acid (IAA), known as one of the main forms of auxin, is able to activate plant immunity. However, it is unknown whether IAA enhances plant resistance and/or suppresses the growth of the fungal pathogen Magnaporthe oryzae. Here, we found that IAA could induce expression levels of pathogenesis-related genes to enhance disease resistance and could control the development of blast disease through inhibiting M. oryzae infection. Exogenous IAA suppressed mycelial growth and delayed spore germination by inhibiting fungal endogenous IAA biosynthesis and impairing redox homeostasis, respectively. When applied to a field test, two IAA analogues, 1-naphthaleneacetic acid and 2,4-dichlorophenoxy acetic acid, can effectively control rice blast disease. Our study advances the understanding of IAA in controlling rice blast disease through suppressing pathogen growth and enhancing plant resistance.

Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.