Glycolytic dysregulation in Alzheimer's disease: unveiling new avenues for understanding pathogenesis and improving therapy.

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer's disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer's disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

Relationship between CCL2 gene 2518A/G (rs1024611) polymorphism and age-related macular degeneration susceptibility: meta-analysis and trial sequential analysis.

PURPOSE: This study aimed to investigate the association between the CC-cytokine ligand-2 (CCL2) 2518A/G (rs1024611) single nucleotide polymorphism (SNP) and susceptibility to age-related macular degeneration (AMD). METHODS: PubMed, Embase, Web of Science, and other databases were searched for articles published before August 24, 2023. After searching, data extraction, and quality assessment, meta-analysis and trial sequential analysis were conducted using RevMan 5.4, Stata 17.0, and TSA 0.9.5.10 Beta software. Combined OR, P values, and 95% confidence intervals (CIs) were calculated. Sensitivity analysis, subgroup analysis and publication bias assessment were also performed. RESULTS: Six articles, comprising 1186 cases and 1124 controls, were included. No significant statistical difference was found in six main outcomes. However, due to observed heterogeneity and high sensitivity, subgroup analysis was performed, revealing statistically significant differences across different regions. No significant publication bias was observed. Trial sequential analysis suggested the need for additional follow-up case-control studies to further validate the findings. CONCLUSION: The CCL2 gene 2518A/G (rs1024611) polymorphism is associated with AMD susceptibility. Among Caucasian populations in West Asia and Europe, the G allele is protective against AMD, whereas in East and South Asia, it poses a risk factor.

MYB52 negatively regulates ADF9-meditated actin filament bundling in Arabidopsis pavement cell morphogenesis.

It has been proposed that cortical fine actin filaments are needed for the morphogenesis of pavement cells (PCs). However, the precise role and regulation mechanisms of actin filaments in PC morphogenesis are not well understood. Here, we found that Arabidopsis thaliana ACTIN DEPOLYMERIZING FACTOR9 (ADF9) is required for the morphogenesis of PC, which is negatively regulated by the R2R3 MYELOBLASTOSIS (MYB) transcription factor MYB52. In adf9 mutants, the lobe number of cotyledon PCs was significantly reduced, while the average lobe length did not differ significantly compared to that of wild type (Col-0), except for the variations in cell area and circularity, whereas the PC shapes in ADF9 overexpression seedlings showed different results. ADF9 decorated actin filaments, and colocalized with plasma membrane. The extent of filament bundling and actin filament bundling activity in adf9 mutant decreased. In addition, MYB52 directly targeted the promoter of ADF9 and negatively regulated its expression. The myb52-2 mutant showed increased lobe number and cell area, reduced cell circularity of PCs, and the PC phenotypes were suppressed when ADF9 was knocked out. Taken together, our data demonstrate that actin filaments play an important role in the morphogenesis of PC and reveal a transcriptional mechanism underlying MYB52 regulation of ADF9-mediated actin filament bundling in PC morphogenesis.

Impact of coronary collateralization on major adverse cardiovascular and cerebrovascular events after successful recanalization of chronic total occlusion.

Aims: This study aims to investigate the effects of coronary collateral circulation (CCC) on the prognosis of chronic total occlusion (CTO) patients with or without metabolic syndrome (MetS). Methods: The study included 342 CTO patients who underwent successful percutaneous coronary intervention at the People's Hospital of Liaoning Province between 1 February 2021 and 30 September 2023. The Rentrop score was used to assess the status of CCC. The outcome was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as a composite of all-cause mortality, cardiac death, non-fatal myocardial infarction (MI), target vessel revascularization (TVR), and non-fatal stroke. Univariate and multivariate logistic analyses were used to investigate the association of CCC, MetS, and MACCEs with odds ratios (ORs) and 95% confidence intervals (CIs). The effect of CCC was further investigated in different MetS, diabetes mellitus (DM), and Syntax score groups. Results: MACCEs were more common in patients with poor CCC compared to those with good CCC (38.74% vs. 16.56%). Statistical differences were found in MACCEs (OR = 3.33, 95% CI: 1.93-5.72), MI (OR = 3.11, 95% CI: 1.73-5.58), TVR (OR = 3.06, 95% CI: 1.70-5.53), and stent thrombosis (OR = 6.14, 95% CI: 2.76-13.65) between the good and poor CCC groups. Poor CCC patients with MetS had a higher incidence of MACCEs (OR = 4.21, 95% CI: 2.05-8.65), non-fatal MI (OR = 4.44, 95% CI: 2.01-9.83), TVR (OR = 3.28, 95% CI: 1.51-7.11), and stent thrombosis (OR = 10.80, 95% CI: 3.11-37.54). Similar findings were also observed in CTO patients with DM and a Syntax score ≥23. Conclusion: Poor CCC could increase the risk of MACCEs in CTO patients, particularly those with MetS, DM, and a Syntax score ≥23. Further prospective, multicenter studies are needed to validate our findings and to explore potential therapeutic interventions.

Unconscious and Conscious Gaze-Triggered Attentional Orienting: Distinguishing Innate and Acquired Components of Social Attention in Children and Adults with Autistic Traits and Autism Spectrum Disorders.

Typically developing (TD) individuals can readily orient attention according to others' eye-gaze direction, an ability known as social attention, which involves both innate and acquired components. To distinguish between these two components, we used a critical flicker fusion technique to render gaze cues invisible to participants, thereby largely reducing influences from consciously acquired strategies. Results revealed that both visible and invisible gaze cues could trigger attentional orienting in TD adults (aged 20 to 30 years) and children (aged 6 to 12 years). Intriguingly, only the ability to involuntarily respond to invisible gaze cues was negatively correlated with autistic traits among all TD participants. This ability was substantially impaired in adults with autism spectrum disorder (ASD) and in children with high autistic traits. No such association or reduction was observed with visible gaze cues. These findings provide compelling evidence for the functional demarcation of conscious and unconscious gaze-triggered attentional orienting that emerges early in life and develops into adulthood, shedding new light on the differentiation of the innate and acquired aspects of social attention. Moreover, they contribute to a comprehensive understanding of social endophenotypes of ASD.

[Association of the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene with preeclampsia among Chinese women].

OBJECTIVE: To assess the association of -c.108C>T and c.192Q>R polymorphisms of paraoxonase 1 (PON1) gene with preeclampsia (PE) and the influence of genotypes on the metabolic and oxidative stress indexes among Chinese women. METHODS: This case-control study has included 334 patients with PE and 1337 healthy pregnant women. The -c.108C>T and c.192Q>R genotypes were determined by PCR and restriction fragment length polymorphism method. Metabolic and oxidative stress parameters were also analyzed. RESULTS: No statistical difference in the genotypic and allelic frequencies for the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene was found between the PE patients and the healthy controls (P > 0.05). Nevertheless, the 192Q-108T haplotype of these polymorphisms was associated with an increased risk of PE (P = 0.007). Total antioxidant capacity (TAC) and atherosderosis index were higher in patients with the -108TT genotype compared with those with a CT genotype (P < 0.05); whilst total oxidant status was lower in patients with a CT genotype compared with those with a CC genotype (P = 0.036). Malondialdehyde level was higher in patients with a 192RR genotype compared with those with a QQ genotype (P = 0.019). TAC level was higher in patients with a RR genotype compared with those with a QR genotype (P = 0.015). CONCLUSION: The 192Q-108T haplotype of the PON1 gene is associated with the risk for PE. These polymorphisms may be associated with abnormal lipid metabolism and oxidative stress among Chinese PE patients.

Graphitic Carbon Nitride Enters the Scene: A Promising Versatile Tool for Biomedical Applications.

Graphitic carbon nitride (g-C3N4), since the pioneering work on visible-light photocatalytic water splitting in 2009, has emerged as a highly promising advanced material for environmental and energetic applications, including photocatalytic degradation of pollutants, photocatalytic hydrogen generation, and carbon dioxide reduction. Due to its distinctive two-dimensional structure, excellent chemical stability, and distinctive optical and electrical properties, g-C3N4 has garnered a considerable amount of interest in the field of biomedicine in recent years. This review focuses on the fundamental properties of g-C3N4, highlighting the synthesis and modification strategies associated with the interfacial structures of g-C3N4-based materials, including heterojunction, band gap engineering, doping, and nanocomposite hybridization. Furthermore, the biomedical applications of these materials in various domains, including biosensors, antimicrobial applications, and photocatalytic degradation of medical pollutants, are also described with the objective of spotlighting the unique advantages of g-C3N4. A summary of the challenges faced and future prospects for the advancement of g-C3N4-based materials is presented, and it is hoped that this review will inspire readers to seek further new applications for this material in biomedical and other fields.

A novel polymer platform for endoscopic tattooing with high efficacy and safety.

Endoscopic tattooing plays a pivotal role in modern endoscopic localization of gastrointestinal lesions, facilitating further surgical intervention and aiding in the postoperative identification and repositioning of lesions. However, traditional endoscopic tattoo dyes often suffer from drawbacks such as side effects, short tattoo duration, and high overall costs. In this study, we developed polyvinylpyrrolidone (PVP)-modified polypyrrole (PPy) nanoparticles by oxidizing pyrrole in a PVP aqueous solution to create a PPy/PVP nanoparticle solution. This innovation aims to enhance endoscopic tattooing efficiency and mitigate the limitations associated with current tattooing methods. Both in vitro and in vivo evaluations confirmed the biosafety of PPy/PVP nanoparticles. Endoscopic tattooing experiments conducted in a pig model demonstrated the dye's stability within the digestive tract. Similarly, subcutaneous tissue tattooing experiments performed in a mouse model revealed the sustained stability of the PPy/PVP tattoo dye for at least 180 days. With its robust stability, safety, and longevity, PPy/PVP nanoparticles hold promise as novel tattoo dyes for marking intestinal lesion sites. This advancement has the potential to enhance the accuracy of lesion localization and long-term tracking.

Blood magnesium level and risk of hepatocellular carcinoma in a prospective liver cirrhosis cohort.

BACKGROUND: Higher magnesium intake was linked to lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among liver cirrhosis patients who are at higher risk for HCC. METHODS: In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,460 liver cirrhosis patients without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazard models to generate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident HCC, and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection. RESULTS: During a median follow-up period of 4.26 years, 109 developed HCC. Magnesium deficiency (<1.70mg/dL; N = 158) was associated with a higher risk of HCC (HR =1.88; 95%CI:1.10-3.22) compared to magnesium sufficiency. This association remained robust in the 1-year lag analysis (HR=2.19; 95%CI:1.12-4.29) and in sensitivity analysis excluding patients with alcoholic liver disease (HR=2.26; 95%CI:1.16-4.42). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (ß=3.74; 95%CI:0.51-6.97), direct bilirubin (ß=0.18; 95%CI:0.01-0.35), and total bilirubin (ß=0.20; 95%CI:0.02-0.37), compared to the highest quartile. CONCLUSIONS: Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarkers changes. IMPACT: If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.

Tangeretin Enhances Muscle Endurance and Aerobic Metabolism in Mice via Targeting AdipoR1 to Increase Oxidative Myofibers.

Slow oxidative myofibers play an important role in improving muscle endurance performance and maintaining body energy homeostasis. However, the targets and means to regulate slow oxidative myofibers proportion remain unknown. Here, we show that tangeretin (TG), a natural polymethoxylated flavone, significantly activates slow oxidative myofibers-related gene expression and increases type I myofibers proportion, resulting in improved endurance performance and aerobic metabolism in mice. Proteomics, molecular dynamics, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) investigations revealed that TG can directly bind to adiponectin receptor 1 (AdipoR1). Using AdipoR1-knockdown C2C12 cells and muscle-specific AdipoR1-knockout mice, we found that the positive effect of TG on regulating slow oxidative myofiber related markers expression is mediated by AdipoR1 and its downstream AMPK/PGC-1α pathway. Together, our data uncover TG as a natural compound that regulates the identity of slow oxidative myofibers via targeting the AdipoR1 signaling pathway. These findings further unveil the new function of TG in increasing the proportion of slow oxidative myofibers and enhancing skeletal muscle performance.

Acid-mediated strategies designed for stretchable and durable polyacrylamide/sodium alginate dual-network hydrogels toward flexible capacitors and wearable sensors.

The utilization of acid as a synthesis assistant provides an effective means to regulate the structure of hydrogels, thereby simplifying the design and preparation process of multifunctional hydrogels. However, there remains a dearth of discourse concerning the utilization of this convenient acid-mediated strategy, which possesses the potential to directly govern molecular interactions within gel networks for rational structure and property design. Herein, we describe the preparation of flexible dual-network conductive hydrogels using polyacrylamide (PAM) and sodium alginate (SA) as substrates, driven by the strategy of acid-mediated (HCI, H2SO4, and H2C2O4) in detail for the first time. Especially, the structure-activity relationship of hydrogels was elucidated through a comparative analysis of molecular dynamics (MD) simulations and empirical properties, thereby enhancing the understanding of this field. Furthermore, extensive investigations have been conducted to explore the distinct impacts of acid ions and concentrations. The acid-mediated method exhibits superior versatility and operability compared to the filler modification method, thereby enabling a more convenient acquisition of conductive and robust hydrogels suitable for flexible capacitors and wearable sensors. Consequently, this study presents a straightforward, efficient, and cost-effective universal strategy for targeted functional hydrogel design.

Non-complete recovery of temporal lobe white matter diffusion metrics at one year Post-Radiotherapy: Implications for Radiation-Induced necrosis risk.

BACKGROUND: Temporal lobe (TL) white matter (WM) injuries are often seen early after radiotherapy (RT) in nasopharyngeal carcinoma patients (NPCs), which fail to fully recover in later stages, exhibiting a "non-complete recovery pattern". Herein, we explored the correlation between non-complete recovery WM injuries and TL necrosis (TLN), identifying dosimetric predictors for TLN-related high-risk WM injuries. METHODS: We longitudinally examined 161 NPCs and 19 healthy controls employing multi-shell diffusion MRI. Automated fiber-tract quantification quantified diffusion metrics within TL WM tract segments. ANOVA identified non-complete recovery WM tract segments one-year post-RT. Cox regression models discerned TLN risk factors utilizing non-complete recovery diffusion metrics. Normal tissue complication probability (NTCP) models and dose-response analysis further scrutinized RT-related toxicity to high-risk WM tract segments. RESULTS: Seven TL WM tract segments exhibited a "non-complete recovery pattern". Cox regression analysis identified mean diffusivity of the left uncinate fasciculus segment 1, neurite density index (NDI) of the left cingulum hippocampus segment 1, and NDI of the right inferior longitudinal fasciculus segment 1 as TLN risk predictors (hazard ratios [HRs] with confidence interval [CIs]: 1.45 [1.17-1.81], 1.07 [1.00-1.15], and 1.15 [1.03-1.30], respectively; all P-values < 0.05). In NTCP models, D10cc.L, D20cc.L and D10cc.R demonstrated superior performance, with TD50 of 37.22 Gy, 24.96 Gy and 37.28 Gy, respectively. CONCLUSIONS: Our findings underscore the significance of the "non-complete recovery pattern" in TL WM tract segment injuries during TLN development. Understanding TLN-related high-risk WM tract segments and their tolerance doses could facilitate early intervention in TLN and improve RT protocols.

Sexual health in transgender and gender diverse people.

PURPOSE OF REVIEW: Sexual health and sexual function are critical to the wellbeing of cisgender, transgender, and gender diverse populations. To date, there has been only limited patient-focused evaluation of sexual function in transgender and gender diverse patients at several stages in their gender-affirming medical care. There remains a need to better understand the impact of gender affirming medical and surgical therapy on sexual health, and to develop evidence-based treatments to address sexual dysfunction when present. RECENT FINDINGS: The impact of gender-affirming hormone therapy on sexual health is complex and evolves over time on treatment. Despite high incidences of complications, major genital gender-affirming surgeries such as vulvovaginoplasty and penile implant placement after phalloplasty yield high patient satisfaction. While treatments to preserve or restore erections and to improve vaginal lubrication have been trialed based upon literature in cisgender populations, there remains minimal evidence to guide medical treatment of sexual dysfunction ranging from erectile dysfunction to dyspareunia. SUMMARY: There is a continued need for ongoing efforts to develop patient-reported outcome measures and rigorous investigation of sexual health preservation and restoration treatments in transgender and gender diverse populations.

How Does Temperature Affect the Charge Transfer Process in Flow Electrode Capacitive Deionization?

In this study, we investigate how temperature variations, a key environmental factor, affect the charge transfer process in FCDI systems across seasonal variation and geographical distributions, which is crucial for optimizing FCDI performance but has not received adequate attention. Therefore, thermal-assisted FCDI systems were proposed by controlling the temperatures of the flow electrode and saline water to simulate the environmental conditions, and the temperature effects on the charge transport and desalting ability of FCDI were investigated. First, the isothermal mode was performed, where the flow electrode and saline water were controlled at the same temperatures (0-50 °C) to simulate the natural atmospheric temperature fluctuations and industrial circulating cooling water system. Experimental results showed a strong positive correlation between temperature and electrosorption dynamics. Elevated temperatures significantly improved ion electromigration and diffusion, thereby enhancing the electrosorption capacity of the FCDI device. On this basis, the nonisothermal mode was designed via maintaining the temperature of the flow electrode at 50 °C to improve the desalination performance of FCDI for saline water at different temperatures (0-50 °C). Finally, the East China seawater and industrial circulating cooling water were both desalted successfully to confirm the feasibility of the temperature field in the practical application of FCDI.

TUG1 exacerbates cerebral ischemia-reperfusion injury through miR-340-5p-mediated PTEN.

Long non-coding RNAs (LncRNAs) play a substantial role in the process of cerebral ischemia-reperfusion injury (CIRI). The present work aimed to determine the probable mechanism by which LncRNA TUG1 exacerbates CIRI via the miR-340-5p/phosphatase and tensin homolog (PTEN) pathway. After developing a middle cerebral artery occlusion/reperfusion (MCAO/R) model, pcDNA-TUG1 together with miR-340-5p agomir were administrated in vivo. Furthermore, the neurologic defects in rats were assessed by a modified neurological severity score. Moreover, 2,3,5-Triphenyl-2 H-tetrazolium chloride stain-step was performed to determine the brain's infarct size. In addition, western blotting, immunohistochemistry, and qRT-PCR experiments were utilized for gauging the proteomic/genomic expression-profiles. Luciferase reporter assay validated correlations across TUG1, miR-340-5p, together with PTEN. The results indicated relatively reduced miR-340-5p levels in MCAO/R models, while upregulated TUG1 levels. The pcDNA-TUG1-treated rats indicated increasing neurological dysfunction, whereas the miR-340-5p agomir-treated rats showed improvement. Furthermore, miR-340-5p was determined to be the expected and confirmed TUG1 target. All things considered, the findings suggested that PTEN can serve as the target of miR-340-5p. In addition, TUG1 served as a miR-340-5p ceRNA, which promotes PTEN modulation. Furthermore, TUG1 overexpression decreased miR-340-5p's capacity to fend against CIRI. Conclusively, this work proved that in CIRI, targeting the TUG1/miR-340-5p/PTEN regulatory axis is a viable approach for the treatment of ischemic stroke.

Mixed-Dimensional Integration of 3D-on-2D Heterostructures for Advanced Electronics.

Two-dimensional (2D) materials have garnered significant attention due to their exceptional properties requisite for next-generation electronics, including ultrahigh carrier mobility, superior mechanical flexibility, and unusual optical characteristics. Despite their great potential, one of the major technical difficulties toward lab-to-fab transition exists in the seamless integration of 2D materials with classic material systems, typically composed of three-dimensional (3D) materials. Owing to the self-passivated nature of 2D surfaces, it is particularly challenging to achieve well-defined interfaces when forming 3D materials on 2D materials (3D-on-2D) heterostructures. Here, we comprehensively review recent progress in 3D-on-2D incorporation strategies, ranging from direct-growth- to layer-transfer-based approaches and from non-epitaxial to epitaxial integration methods. Their technological advances and obstacles are rigorously discussed to explore optimal, yet viable, integration strategies of 3D-on-2D heterostructures. We conclude with an outlook on mixed-dimensional integration processes, identifying key challenges in state-of-the-art technology and suggesting potential opportunities for future innovation.

Chitosan-modified molybdenum selenide mediated efficient killing of Helicobacter pylori and treatment of gastric cancer.

Helicobacter pylori (H. pylori) is one of the major causes of gastrointestinal diseases, including gastric cancer. However, the acidic environment of the stomach and H. pylori resistance severely impair the antimicrobial efficacy of oral drugs. Here, a biocompatible chitosan-modified molybdenum selenide (MoSe2@CS) was designed for the simultaneous photothermal treatment of H. pylori infection and gastric cancer. MoSe2@CS showed a photothermal conversion efficiency was as high as 45.7 %. In the H. pylori-infected mice model, MoSe2@CS displayed a high bacteriostasis ratio of 99.9 % upon near-infrared irradiation. The antimicrobial functionality was also proved by transcriptomic sequencing study, which showed that MoSe2@CS combined with NIR laser irradiation modulated the gene expression of a variety of H. pylori bioprocesses, including cell proliferation and inflammation-related pathways. Further gut flora analysis results indicated that MoSe2@CS mediated PTT of H. pylori did not affect the homeostasis of gut flora, which highlights its advantages over traditional antibiotic therapy. In addition, MoSe2@CS exhibited a good photothermal ablation effect and significantly inhibited gastric tumor growth in vitro and in vivo. The comprehensive application of MoSe2@CS in the PTT of H. pylori infection and gastric cancer provides a new avenue for the clinical treatment of H. pylori infection and related diseases.

Palmitoylethanolamide-Incorporated Elastic Nano-Liposomes for Enhanced Transdermal Delivery and Anti-Inflammation.

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application.

TGFß-mediated inhibition of hypodermal adipocyte progenitor differentiation promotes wound-induced skin fibrosis.

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFß pathway signature. TGFß was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFß receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFß pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFß-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

Construction of oral squamous cell carcinoma organoids in vitro 3D-culture for drug screening.

OBJECTIVE: Patient-derived organoids are potent pre-chemotherapy models. Due to limited research on diverse types of oral squamous cell carcinoma (OSCC) and construction efficiency, our goal was to optimize OSCC organoid models from various sites and assess drug responsiveness. METHODS: We screened and optimized culture media, employing three-dimensional techniques to construct human-derived oral squamous cell carcinoma (OSCC) organoid models in vitro. Morphological validation, immunofluorescence analysis, tissue origin verification, and Short Tandem Repeat (STR) sequencing confirmed the consistency between organoids and source tissues. These organoid models were then subjected to varying concentrations of anticancer drugs, with subsequent assessment of cell viability to calculate IC50 values. RESULTS: Twenty-nine surgical specimens yielded an 86.2% success rate in culturing 25 organoids in vitro. Morphological consistency confirmed nuclear atypia and positive expression of K5, P40, and E-cadherin, indicating squamous epithelial origin. Cultured complex organoids included α-SMA+ tumour-associated fibroblasts and tumour stem cells expressing CD44 and Ki67. STR sequencing affirmed genomic homogeneity between cultured organoids and source tissues. Drug sensitivity testing revealed diverse responses among organoids, highlighting their value for assessing drug sensitivity. CONCLUSIONS: An efficient OSCC organoid culture system for personalized in vitro drug sensitivity screening was established, laying the foundation for precise treatment development.