A radiomics model for predicting perineural invasion in stage II-III colon cancer based on computer tomography.

BACKGROUND: Colon cancer, a frequently encountered malignancy, exhibits a comparatively poor survival prognosis. Perineural invasion (PNI), highly correlated with tumor progression and metastasis, is a substantial effective predictor of stage II-III colon cancer. Nonetheless, the lack of effective and facile predictive methodologies for detecting PNI prior operation in colon cancer remains a persistent challenge. METHOD: Pre-operative computer tomography (CT) images and clinical data of patients diagnosed with stage II-III colon cancer between January 2015 and December 2023 were obtained from two sub-districts of Sun Yat-sen Memorial Hospital (SYSUMH). The LASSO/RF/PCA filters were used to screen radiomics features and LR/SVM models were utilized to construct radiomics model. A comprehensive model, shown as nomogram finally, combining with radiomics score and significant clinical features were developed and validated by area under the curve (AUC) and decision curve analysis (DCA). RESULT: The total cohort, comprising 426 individuals, was randomly divided into a development cohort and a validation cohort as a 7:3 ratio. Radiomics scores were extracted from LASSO-SVM models with AUC of 0.898/0.726 in the development and validation cohorts, respectively. Significant clinical features (CA199, CA125, T-stage, and N-stage) were used to establish combining model with radiomics scores. The combined model exhibited superior reliability compared to single radiomics model in AUC value (0.792 vs. 0.726, p = 0.003) in validation cohorts. The radiomics-clinical model demonstrated an AUC of 0.918/0.792, a sensitivity of 0.907/0.813 and a specificity of 0.804/0.716 in the development and validation cohorts, respectively. CONCLUSION: The study developed and validated a predictive nomogram model combining radiomics scores and clinical features, and showed good performance in predicting PNI pre-operation in stage II-III colon cancer patients.

Pharmacodynamic and pharmacokinetic study of Shaoyao Gancao decoction for repairing intestinal barrier damage in ulcerative colitis.

OBJECTIVE: To study the therapeutic effect and mechanism of Shaoyao Gancao Decoction (SGD) on ulcerative colitis (UC) mice based on the perspective of intestinal barrier, and this study provides a new consultation for the clinical application of SGD. METHODS: The chemical composition of SGD was characterized by HPLC. The UC mouse model was constructed by 3 % dextran sodium sulfate (DSS), which were randomly divided into the model group (DSS), the positive drug group (5-ASA), the Shaoyao group (SYD), Gancao group (GCD), and the Shaoyao Gancao Decoction group (SGD) at low, medium, and high dosages, respectively. The effects of each drug treatment group on UC were evaluated by the rate of body weight loss, disease activity index (DAI), colon length, spleen index, histopathological evaluations, and the levels of serum inflammatory factors (IL-1ß, IL-6, IL-10, IL-21, and TNF-α). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining, ELISA was used to detect the content of LPS in serum, and Western blot was used to detect the changes in the expression of tight junction proteins ZO-1, occludin, and the pathway proteins TLR4 and NF-κBp65 in the colonic tissues, to explore the protective effect of SGD on the intestinal barrier of UC mice. The vivo absorption process of the main active ingredients in the SG, SY and GC groups was determined by LC-MS. RESULTS: The contents of albiflorin, paeoniflorin, liquiritin apioside, liquiritin and glycyrrhetinic acid were 6.1227 mg/g, 20.8993 mg/g, 4.0054 mg/g, 3.6140 mg/g and 8.2515 mg/g, respectively. Compared with DSS group, SGD reduced weight loss(P<0.01) and DAI scores(P<0.05), prevented colon shortening(P<0.01), and ameliorated histopathological damage of the colon in UC mice(P<0.01). SGD also protected the intestinal barrier to alleviate UC by significantly reducing serum LPS and inflammatory factor levels, altering the number of goblet cells, promoting tight junction proteins (ZO-1 and occludin) and decreasing the expression of TLR4 and NF-κB in colonic tissues. Pharmacokinetic results showed that there was no significant difference in Cmax, AUC0-t (µg/L.h) and Tmax of albiflorin and paeoniflorin between the SY and SG groups, the Tmax was within 1 h; the AUC0-t (µg/L.h) of liquiritin and glycyrrhizic acid were about 1.6 and 1.9 times higher in the SG group compared to the GC group, respectively. The Cmax, Tmax and AUC0-t (µg/L.h) of glycyrrhizinic acid were significantly reduced to 0.73, 0.68 and 0.68 times of that of the GC group. CONCLUSION: SGD may have a therapeutic effect on DSS-induced UC mice by repairing the damaged intestinal barrier through the TLR4/NF-κB pathway. The combination of Shaoyao and Gancao increased the absorption of liquiritin and glycyrrhizic acid in vivo. The combination of Shaoyao and Gancao could promote the absorption of Gancao, and that the pairing of the two herbs could have a synergistic effect.

Experimental investigation of zinc ferrite/insulation oil nanofluid natural convection heat transfer, AC dielectric breakdown voltage, and thermophysical properties.

Improving the thermal and dielectric properties of insulation oil (INO) with nanoadditives is an important challenge, and achieving dispersion stability in these nanofluids is quite challenging, necessitating further investigation. The main goal of this study is the synthesis and use of the hydrophobicity of zinc ferrite (ZnFe2O4) nanoparticles, which can improve both the thermal and dielectric properties of the INO. This oil is made from distillate (petroleum), including severely hydrotreated light naphthenic oil (75-85%) and severely hydrotreated light paraffinic oil (15-25%). A comprehensive investigation was carried out, involving the creation of nanofluids with ZnFe2O4 nanoparticles at various concentrations, and employing various characterization methods such as X-ray diffraction (XRD), Fourier-transform infrared (FTIR), scanning electron microscopy, energy dispersive X-ray (EDX), zeta potential analysis, and dynamic light scattering (DLS). The KD2 Pro thermal analyzer was used to investigate the thermal characteristics, including the thermal conductivity coefficient (TCC) and volumetric heat capacity (VHC). Under free convection conditions, the free convection heat transfer coefficient (FCHTC) and Nusselt numbers (Nu) were evaluated, revealing enhancements ranging from 14.15 to 11.7%. Furthermore, the most significant improvement observed in the AC Breakdown voltage (BDV) for nanofluids containing 0.1 wt% of ZnFe2O4 amounted to 17.3%. The most significant finding of this study is the improvement in the heat transfer performance, AC BDV, and stability of the nanofluids.

USP19 exerts a tumor-promoting role in diffuse large B cell lymphoma through stabilizing PARK7.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and is associated with a poor prognosis. Data from the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed dysregulated expression of several ubiquitin-specific proteases (USPs) in DLBCL tissues (DLBCL vs. non-DLBCL = 47 vs. 337), including USP19 (log2fold change = 1.17, P < 0.05). USP19 is closely linked to tumorigenesis, but its role in DLBCL progression remains largely unknown. Here, we investigated the role of USP19 in DLBCL development. Genetic manipulation of USP19 using adenovirus-based vectors was performed in two DLBCL cell lines, SUDHL4 and DB cells. The results showed that USP19 knockdown suppressed the proliferation, anchorage-independent growth and xenograft tumor formation of DLBCL cells and arrested the cell cycle at the G1 stage. In parallel, DLBCL cells overexpressing USP19 acquired a more malignant phenotype. Next, to explore USP19 interactors, we performed co-immunoprecipitation/liquid chromatography-mass spectrometry and identified potential interacting proteins. Among them, Parkinson disease protein 7 (PARK7), a member of the peptidase C56 family known to be involved in carcinogenesis, was further validated to bind with and be stabilized by USP19. Additionally, we found that USP19 induced PARK7 deubiquitylation in both DLBCL cell lines, and PARK7 acted as a downstream effector of USP19 in regulating the growth of DLBCL cells. Collectively, USP19 exerts a tumor-promoting role in DLBCL through interacting with and stabilizing PARK7.

Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques.

As an essential transcriptional activator, PDX1 plays a crucial role in pancreatic development and ß-cell function. Mutations in the PDX1 gene may lead to type 4 maturity-onset diabetes of the young (MODY4) and neonatal diabetes mellitus. However, the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models. In this study, three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology, all of which succumbed shortly postpartum, exhibiting pancreatic agenesis. Notably, one tri-allelic PDX1-mutant cynomolgus macaque (designated as M4) developed a pancreas, whereas the two mono-allelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation. RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions, indicating developmental delay and PDX1 haploinsufficiency. A marked change in m6A methylation was identified in the M4 pancreas, confirmed through cultured PDX1-mutant islet organoids. Notably, overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids. This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury.

Spinal cord injury (SCI) results in numerous systemic dysfunctions, including intestinal dysmotility and enteric nervous system (ENS) atrophy. The ENS has capacity to recover following perturbation, yet intestinal pathologies persist. With emerging evidence demonstrating SCI-induced alterations to gut microbiome composition, we hypothesized that microbiome modulation contributes to post-injury enteric recovery. Here, we show that intervention with the dietary fiber, inulin, prevents SCI-induced ENS atrophy and dysmotility in mice. While SCI-associated microbiomes and specific injury-sensitive gut microbes are not sufficient to modulate intestinal dysmotility after injury, intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions in injured mice. Notably, inulin-mediated resilience is dependent on IL-10 signaling, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience post-injury. Overall, we demonstrate that diet and microbially-derived signals distinctly impact ENS survival after traumatic spinal injury and represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

A new perspective on proteinuria and drug therapy for diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter two inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists, have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease, providing a new perspective on the clinical diagnosis and treatment of DKD.

Elderly patients with dysphagia in the intensive care unit: Association between malnutrition and delirium.

BACKGROUND: Dysphagia, as a geriatric syndrome, is prevalent in the intensive care unit (ICU). Malnutrition resulting from swallowing disorders is likely to correlate with adverse ICU outcomes, including delirium, thereby escalating the costs of care and hospitalization. However, malnutrition has not received the attention it deserves in ICU clinical nursing practice. As two preventable and correctable conditions-malnutrition and delirium-the advantages of early identification and intervention are substantial. Exploring the relationship between malnutrition and delirium, starting from the high-risk group of elderly patients with swallowing difficulties in the ICU, will aid us in managing patients promptly and effectively. AIM: To investigate the relationship between malnutrition and the incidence of delirium in elderly patients with dysphagia in the ICU. SUDY DESIGN: This is a retrospective study. Data for this study were obtained from the Medical Information Mart for Intensive Care-IV. All 2273 patients included were dysphagia older patients over 65 years of age admitted to the ICU, and logistic regression was used to explore the relationship between malnutrition and delirium. We also used propensity score matching (PSM) for sensitivity analysis. RESULTS: Among the included patients with swallowing difficulties, 13% individuals (297/2273) exhibited malnutrition, with a delirium incidence rate of 55.9% (166/297). In the non-malnutrition group (1976/2273), the delirium incidence rate is 35.6% (704/1976). After adjusting for 31 covariates, multifactorial logistic regression showed that malnutrition was significantly positively associated with the incidence of delirium in elderly dysphagic patients in the ICU (adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.47-2.62). The results remained stable after analysis by PSM. CONCLUSION: Malnutrition was significantly positively associated with the incidence of delirium in elderly dysphagic patients in the ICU. Malnutrition should be given adequate attention in the ICU. RELEVANCE TO CLINICAL PRACTICE: ICU nurses should pay particular attention to malnutrition, especially among the high-prevalence group of patients with dysphagia. Early identification and nutritional intervention for these patients may help reduce the costs of care and health care expenditures.

Influence of sodium/glucose cotransporter-2 inhibitors on the incidence of acute kidney injury: a meta-analysis.

Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are associated with cardiovascular benefits. The aim of this systematic review and meta-analysis is to summarize the influence of SGLT2i on the incidence of acute kidney injury (AKI), and to ascertain whether it is affected by confounding variables such as age, baseline renal function and concurrent use of renin-angiotensin-aldosterone system inhibitors (RAASi) or mineralocorticoid receptor antagonists (MRA). Methods: PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials comparing the influence of SGLT2i versus placebo/blank treatment on AKI in the adult population. A fixed-effect model was used if the heterogeneity was not significant; otherwise, a randomized-effect model was used. Results: Eighteen studies comprising 98,989 patients were included. Compared with placebo/blank treatment, treatment with SGLT2i significantly reduced the risk of AKI (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.71 to 0.84, p < 0.001; I 2 = 0%). Subgroup analysis suggested consistent results in patients with diabetes, chronic kidney disease, and heart failure (for subgroup difference, p = 0.32). Finally, univariate meta-regression suggested that the influence of SGLT2i on the risk of AKI was not significantly modified by variables such as age (coefficient: 0.011, p = 0.39), baseline estimated glomerular filtration rate (coefficient: -0.0042, p = 0.13) or concomitant use of RAASi (coefficient: 0.0041, p = 0.49) or MRA (coefficient: -0.0020, p = 0.34). Conclusion: SGLT2i may be effective in reducing the risk of AKI, and the effect might not be modified by age, baseline renal function and concurrent use of RAASi or MRA.

Extracellular vesicle-packaged lncRNA from cancer-associated fibroblasts promotes immune evasion by downregulating HLA-A in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer-associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF-derived extracellular vesicle (EV)-packaged long non-coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV-packaged lncRNA RP11-161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA-A expression, a key component of antigen presentation. Mechanistically, RP11-161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4-NOT complex, enhancing the degradation of HLA-A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti-tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA-based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF-derived EV-packaged lncRNA RP11-161H23.5/CNOT4/HLA-A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury.

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

SLC7A2-Mediated Lysine Catabolism Inhibits Immunosuppression in Triple Negative Breast Cancer.

Breast cancer is one of the most common malignant tumors worldwide. SLC7A2 is abnormally expressed in multiple cancers. However, its potential in triple negative breast cancer (TNBC) is still unclear. The purpose of this study was to investigate the roles of SLC7A2 and its underlying molecular mechanisms in TNBC. mRNA expression was detected by RT-qPCR. Protein expression was detected by western blot. Co-localization of ACOX1 and TCF1 was determined using FISH assay. Histone crotonylation was performed using in vitro histone crotonylation assay. Functional analysis was performed using CCK-8 and flow cytometry assays. Xenograft assay was conducted to further verify the role of SLC7A2 in TNBC. CD8A expression was detected using immunohistochemistry. We found that SLC7A2 is downregulated in TNBC tumors. Low levels are associated with advanced stages and lymph node metastasis. SLC7A2 expression is positively correlated with CD8A. SLC7A2-mediated lysine catabolism drives the activation of CD8+ T cells. Moreover, SLC7A2 promotes histone crotonylation via upregulating ACOX1. It also promotes interaction between ACOX1 and TCF1, thus promoting antitumor T cell immunity. Additionally, overexpression of SLC7A2 activates CD8+ T cells and enhances the chemosensitivity of anti-PD-1 therapies in vivo. In conclusion, SLC7A2 may function as an antitumor gene in TNBC by activating antitumor immunity, suggesting SLC7A2/ACOX1/TCF1 signaling as a promising therapeutic strategy.

The NF-κB/FXR/TonEBP pathway protects renal medullary interstitial cells against hypertonic stress.

Farnesoid X receptor (FXR), a ligand-activated transcription factor, plays an important role in maintaining water homeostasis by up-regulating aquaporin 2 (AQP2) expression in renal medullary collecting ducts; however, its role in the survival of renal medullary interstitial cells (RMICs) under hypertonic conditions remains unclear. We cultured primary mouse RMICs and found that the FXR was expressed constitutively in RMICs, and that its expression was significantly up-regulated at both mRNA and protein levels by hypertonic stress. Using luciferase and ChIP assays, we found a potential binding site of nuclear factor kappa-B (NF-κB) located in the FXR gene promoter which can be bound and activated by NF-κB. Moreover, hypertonic stress-induced cell death in RMICs was significantly attenuated by FXR activation but worsened by FXR inhibition. Furthermore, FXR increased the expression and nuclear translocation of hypertonicity-induced tonicity-responsive enhance-binding protein (TonEBP), the expressions of its downstream target gene sodium myo-inositol transporter (SMIT), and heat shock protein 70 (HSP70). The present study demonstrates that the NF-κB/FXR/TonEBP pathway protects RMICs against hypertonic stress.

Glycolysis and tumor progression promoted by the m6A writer VIRMA via m6A-dependent upregulation of STRA6 in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, highlighting the urgent need to elucidate the underlying oncogenic mechanisms. VIRMA is a classic isoform of methyltransferases that participates in epigenetic transcriptomic modification in eukaryotic mRNAs. However, the exact roles of VIRMA in PDAC remain unclear. Here, we identified that VIRMA is highly expressed in PDAC, and histone modifications of the promoter may partly account for this dysregulation. Moreover, VIRMA is closely related to glycolysis and poor prognosis in PDAC. We further determined that STRA6 is a direct downstream target of VIRMA in PDAC by RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq). VIRMA is involved in gene expression regulation via 3' UTR targeting of STRA6 mRNA. Furthermore, the m6A reader IGF2BP2 was shown to critically contribute to the stability of STRA6 mRNA. We describe the role of VIRMA in promoting signaling via the STRA6/STAT3 axis, which results in increased levels of HIF-1α, a key activator of glycolysis. In vivo and in vitro experiments reveal that the VIRMA-STRA6-STAT3-HIF-1α axis plays an instrumental role in glycolysis and tumor progression in PDAC. In conclusion, we demonstrate that VIRMA can increase glycolysis in PDAC by upregulating STRA6, a cell surface membrane protein that stimulates the STAT3 pathway, thereby activating HIF-1α and leading to pancreatic cancer malignancy. Overall, our data strongly suggest that the VIRMA-STRA6-STAT3-HIF-1α axis is a viable therapeutic target in PDAC.

Ultrasound Stimulation Attenuates CRS-Induced Depressive Behavior by Modulating Dopamine Release in the Prefrontal Cortex.

Depression is one of the most serious mental disorders affecting modern human life and is often caused by chronic stress. Dopamine system dysfunction is proposed to contribute to the pathophysiology of chronic stress, especially the ventral tegmental area (VTA) which mainly consists of dopaminergic neurons. Focused ultrasound stimulation (FUS) is a promising neuromodulation modality and multiple studies have demonstrated effective ultrasonic activation of cortical, subcortical, and related networks. However, the effects of FUS on the dopamine system and the potential link to chronic stress-induced depressive behaviors are relatively unknown. Here, we measured the effects of FUS targeting VTA on the improvement of depression-like behavior and evaluated the dopamine concentration in the downstream region - medial prefrontal cortex (mPFC). We found that targeting VTA FUS treatment alleviated chronic restraint stress (CRS) -induced anhedonia and despair behavior. Using an in vivo photometry approach, we analyzed the dopamine signal of mPFC and revealed a significant increase following the FUS, positively associated with the improvement of anhedonia behavior. FUS also protected the dopaminergic neurons in VTA from the damage caused by CRS exposure. Thus, these results demonstrated that targeting VTA FUS treatment significantly rescued the depressive-like behavior and declined dopamine level of mPFC induced by CRS. These beneficial effects of FUS might be due to protection in the DA neuron of VTA. Our findings suggest that FUS treatment could serve as a new therapeutic strategy for the treatment of stress-related disorders.

Construction of various lipid carriers to study the transdermal penetration mechanism of sinomenine hydrochloride.

OBJECTIVE: To investigate the transdermal mechanisms and compare the differences in transdermal delivery of Sinomenine hydrochloride (SN) between solid lipid nanoparticles (SLN), liposomes (LS), and nanoemulsions (NE). METHODS: SN-SLN, SN-LS and SN-NE were prepared by ultrasound, ethanol injection and spontaneous emulsification, respectively. FTIR, DSC, in vitro skin penetration, activation energy (Ea) analysis were used to explore the mechanism of drug penetration across the skin. RESULTS: The particle size and encapsulation efficiency were 126.60 nm, 43.23 ± 0.48%(w/w) for SN-SLN, 224.90 nm, 78.31 ± 0.75%(w/w) for SN-LS, and 83.22 nm, 89.01 ± 2.16%(w/w) for SN-LS. FTIR and DSC showed the preparations had various levels of impacts on the stratum corneum's lipid structure which was in the order of SLN > NE > LS. Ea values of SN-SLN, SN-LS, and SN-NE crossing the skin were 2.504, 1.161, and 2.510 kcal/mol, respectively. CONCLUSION: SLN had a greater degree of alteration on the skin cuticle, which allows SN to permeate skin more effectively.

Tumor-associated macrophages drive glycolysis through the IL-8/STAT3/GLUT3 signaling pathway in pancreatic cancer progression.

Glycolytic metabolism is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and tumor-associated stromal cells play important roles in tumor metabolism. We previously reported that tumor-associated macrophages (TAMs) facilitate PDAC progression. However, little is known about whether TAMs are involved in regulating glycolysis in PDAC. Here, we found a positive correlation between CD68+ TAM infiltration and FDG maximal standardized uptake (FDG SUVmax) on PET-CT images of PDAC. We discovered that the glycolytic gene set was prominently enriched in the high TAM infiltration group through Gene Set Enrichment Analysis using The Cancer Genome Atlas database. Mechanistically, TAMs secreted IL-8 to promote GLUT3 expression in PDAC cells, enhancing tumor glycolysis both in vitro and in vivo, whereas this effect could be blocked by the IL-8 receptor inhibitor reparixin. Furthermore, IL-8 promoted the translocation of phosphorylated STAT3 into the nucleus to activate the GLUT3 promoter. Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

Chinese herb couple against diabetes: integrating network pharmacology and mechanism study.

Cassia twig is a dry twig of Cinnamomum cassia Presl, a Lauraceae plant. Astragalus L is one of the largest genuses of flowering plants in the Leguminosae family. Roots of A. membranaceus Bge. var. mongholicus (Bge.) Hsiao, A. membranaceus (Fisch.) Bge. Chinese herb couple refers to the matching of two herbs in pairs, mostly with synergistic effects or toxicity reduction. This Chinese herb couple (Cassia twig-Astragalus) come from the classic famous book "Zhang Xichun's book on Chinese herb couple", which is widely used to treat diabetes. Moreover, both Cassia twig and Astragalus belong to the homology of medicine and food. However, its mechanism is still unclear. The study identified the effective components of Cassia twig-Astragalus by UPLC-Q-TOF-MS/MS and investigated the mechanism of Cassia twig-Astragalus in treating diabetes by virtue of network pharmacology, molecular docking and experimental verification. Firstly, based on UPLC-Q-TOF-MS/MS and network pharmacology, a total of 10 active ingredients of Astragalus and 6 active ingredients of Cassia twig were screened, and a total of 13 key targets were obtained. There were 64 targets at the intersection of Cassia twig-Astragalus with diabetes, mainly including IL-17, TNF, NF-κß, AGE-RAGE signaling pathway, etc. It mainly involves the response of cells to insulin stimulation, the response to insulin and the positive regulation of cell adhesion. Secondly, molecular docking results showed that quercetin has good binding activities with AKT1 and TNF. Calycosin has good binding activities with AKT1, TNF and CAV1. Formononetin has good binding activities with TNF and IL-6. Isorhamnetin has good binding activities with AKT1, TNF and IL-6. Finally, the animal experiments showed that Cassia twig-Astragalus could improve the body weight, blood glucose and glucose tolerance in diabetic rats. After the intervention with Cassia twig-Astragalus, the inflammatory factors (IL-10, TNF-α, IL-6) were significantly improved in diabetic rats, which also effectively reduced TG and TC.Communicated by Ramaswamy H. Sarma.

Validity and applicability of the global leadership initiative on malnutrition criteria in non-dialysis patients with chronic kidney disease.

Introduction: There are no standardized assessment criteria for selecting nutritional risk screening tools or indicators to assess reduced muscle mass (RMM) in the Global Leadership Initiative on Malnutrition (GLIM) criteria. We aimed to compare the consistency of different GLIM criteria with Subjective Global Assessment (SGA) and protein-energy wasting (PEW). Methods: In this study, nutritional risk screening 2002 first four questions (NRS-2002-4Q), Nutritional Risk Screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), and Mini-Nutritional Assessment Short-Form (MNA-SF) tools were used as the first step of nutritional risk screening for the GLIM. The RMM is expressed using different metrics. The SGA and PEW were used to diagnose patients and classify them as malnourished and non-malnourished. Kappa (κ) tests were used to compare the concordance between the SGA, PEW, and GLIM of each combination of screening tools. Results: A total of 157 patients were included. Patients with Chronic kidney disease (CKD) stage 1-3 accounted for a large proportion (79.0%). The prevalence rates of malnutrition diagnosed using the SGA and PEW were 18.5% and 19.7%, respectively. The prevalence of GLIM-diagnosed malnutrition ranges from 5.1% to 37.6%, depending on the different screening methods for nutritional risk and the different indicators denoting RMM. The SGA was moderately consistent with the PEW (κ = 0.423, p < 0.001). The consistency among the GLIM, SGA, and PEW was generally low. Using the NRS-2002-4Q to screen for nutritional risk, GLIM had the best agreement with SGA and PEW when skeletal muscle index (SMI), fat-free mass index (FFMI), and hand grip strength (HGS) indicated a reduction in muscle mass (SGA: κ = 0.464, 95% CI 0.28-0.65; PEW: κ = 0.306, 95% CI 0.12-0.49). Conclusion: The concordance between the GLIM criteria and the SGA and PEW depended on the screening tool used in the GLIM process. The inclusion of RMM in the GLIM framework is important. The addition of HGS could further improve the performance of the GLIM standard compared to the use of body composition measurements.

Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti-PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.