Obesity-driven mitochondrial dysfunction in human adipose tissue-derived mesenchymal stem/stromal cells involves epigenetic changes.

Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.

Circulating microRNA profile of long-lived Okinawans identifies novel potential targets for optimizing lifespan and health span.

Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post-transcriptional level, are differentially regulated in the circulatory system of young, middle-aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50-80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT - common vs. GT - longevity) and validated the findings through RT-qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF-ß, FoxO, AMPK, Pi3K-Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity.

A comparative study of locking plate combined with minimally invasive plate osteosynthesis and intramedullary nail fixation in the treatment of Neer classification of two-part and three-part fractures of the proximal humerus.

OBJECTIVE: To compare the clinical efficacy of the minimally invasive locking plate technique (Philos plate) and interlocking intramedullary nailing technique (TRIGEN intramedullary nail) in the treatment of Neer two-part and three-part proximal humeral fractures. METHODS AND MATERIALS: The clinical data of 60 patients with Neer two-part and three-part proximal humerus fractures admitted to the hospital from April 2017 to April 2021 were retrospectively analyzed. Thirty-two patients were treated with the minimally invasive locking plate technique (minimally invasive plate group), and 28 patients were treated with the interlocking intramedullary nailing technique (intramedullary nail group). The operation time, intraoperative blood loss, incision length, fracture healing time, and postoperative complications were compared between the two groups. The ASES score and Constant-Murley score were used to evaluate the shoulder joint function of the two groups one year after surgery. RESULTS: All 60 patients were followed up for 12 to 24 months, with an average of 16 months. There was no significant difference in operation time, intraoperative blood loss, incision length, or fracture healing time between the two groups (P > 0.05). The incidence of postoperative complications in the intramedullary nail group was significantly lower than that in the minimally invasive steel plate group, and the difference between the groups was statistically significant (P < 0.05). There was no significant difference in the ASES score or Constant-Murley score between the two groups one year after surgery (P > 0.05). CONCLUSION: The use of the minimally invasive locking plate technique and interlocking intramedullary nailing technique in the treatment of Neer two-part and three-part proximal humerus fractures has the advantages of a small incision, less blood loss, and a high fracture healing rate, and both can achieve satisfactory clinical effects. The internal nail technique is more convenient than the minimally invasive locking plate technique in controlling postoperative complications.

ALKBH5-mediated m6A modification of circFOXP1 promotes gastric cancer progression by regulating SOX4 expression and sponging miR-338-3p.

Circular RNAs (circRNAs) have recently been suggested as potential functional modulators of cellular physiology processes in gastric cancer (GC). In this study, we demonstrated that circFOXP1 was more highly expressed in GC tissues. High circFOXP1 expression was positively associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis in patients with GC. Cox multivariate analysis revealed that higher circFOXP1 expression was an independent risk factor for disease-free survival (DFS) and overall survival (OS) in GC patients. Functional studies showed that increased circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, the knockdown of circFOXP1 inhibited tumor growth. Mechanistically, we observed ALKBH5-mediated m6A modification of circFOXP1 and circFOXP1 promoted GC progression by regulating SOX4 expression and sponging miR-338-3p in GC cells. Thus, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for GC.

Mandibular Osteomyelitis as the Earliest Clinical Manifestation of Maxillary Sinus Lymphoma.

Extranodal natural killer/T-cell lymphoma is a distinct subtype of non-Hodgkin lymphoma that originates from natural killer cells or cytotoxic T cells. Its diagnosis is challenging due to the rarity and lack of awareness, especially in cases where osteomyelitis of the jawbone is the initial symptom. This paper reports a case of extranodal natural killer/T-cell lymphoma presenting primarily with oral ulcers. Through analyzing the clinical and pathological characteristics, differential diagnosis, treatment and prognosis, and reasons for misdiagnosis of the disease, this study aims to provide references for clinical diagnosis and treatment.

PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival.

NK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance functionality or expansion for 10-14 days to increase both their activity and quantity. Attaining a robust methodology to produce large doses of potent NK cells for an off-the-shelf product is highly desirable. Notably, past reports have shown that stimulating NK cells with IL-12, IL-15, and IL-18 endows them with memory-like properties, better anti-tumor activity, and persistence. While this approach produces NK cells with clinically favorable characteristics supported by encouraging early results for the treatment of hematological malignancies, its limited scalability, variability in initial doses, and the necessity for patient-specific production hinder its broader application. In this study, stimulation of NK cells with PM21-particles derived from K562-41BBL-mbIL21 cells was combined with memory-like induction using cytokines IL-12, IL-15, and IL-18 to produce NK cells with enhanced anti-tumor function. The use of cytokines combined with PM21-particles (cytokine and particle, CAP) significantly enhanced NK cell expansion, achieving a remarkable 8,200-fold in 14 days. Mechanistically, this significant improvement over expansion with PM21-particles alone was due to the upregulation of receptors for key stimulating ligands (4-1BBL and IL-2), resulting in a synergy that drives substantial NK cell growth, showcasing the potential for more effective therapeutic applications. The therapeutic potential of CAP-NK cells was demonstrated by the enhanced metabolic fitness, persistence, and anti-tumor function both in vitro and in vivo. Finally, CAP-NK cells were amenable to current technologies used in developing therapeutic NK cell products, including CRISPR/Cas9-based techniques to generate a triple-gene knockout or a gene knock-in. Taken together, these data demonstrate that the addition of cytokines enhanced the already effective method of ex vivo generation of therapeutic NK cells with PM21-particles, yielding a superior NK cell product for manufacturing efficiency and potential therapeutic applications.

Role of umbilical cord mesenchymal stromal cells in skin rejuvenation.

Aging is the main cause of many degenerative diseases. The skin is the largest and the most intuitive organ that reflects the aging of the body. Under the interaction of endogenous and exogenous factors, there are cumulative changes in the structure, function, and appearance of the skin, which are characterized by decreased synthesis of collagen and elastin, increased wrinkles, relaxation, pigmentation, and other aging characteristics. skin aging is inevitable, but it can be delayed. The successful isolation of mesenchymal stromal cells (MSC) in 1991 has greatly promoted the progress of cell therapy in human diseases. The International Society for Cellular Therapy (ISCT) points out that the MSC is a kind of pluripotent progenitor cells that have self-renewal ability (limited) in vitro and the potential for mesenchymal cell differentiation. This review mainly introduces the role of perinatal umbilical cord-derived MSC(UC-MSC) in the field of skin rejuvenation. An in-depth and systematic understanding of the mechanism of UC-MSCs against skin aging is of great significance for the early realization of the clinical transformation of UC-MSCs. This paper summarized the characteristics of skin aging and summarized the mechanism of UC-MSCs in skin rejuvenation reported in recent years. In order to provide a reference for further research of UC-MSCs to delay skin aging.

Strong cation-exchange combined with mass spectrometry reveals the glycoform heterogeneity of sialylated glycoproteins.

Sialylation is an important modification of proteins, related to protein life and bioactivity. However, the evaluation of sialylation is only based on the average molecular composition by peptide mapping and glycan profiling because sialylated proteins are usually too heterogeneous to obtain good quality mass spectra by conventional intact mass analysis methods. In this study, a simple strong cation exchange-mass spectroscopy (SCX-MS) method was developed for intact mass analysis of sialylated glycoproteins. The developed SCX-MS method provided good separation for sialylated glycoproteins and had an inherent characteristic of native MS. Thus, the intact mass analysis of highly heterogeneous glycoprotein, which cannot be obtained by reversed-phase liquid chromatography (RPLC)-MS and size exclusion chromatography (SEC)-MS methods, can be well analyzed using the current SCX-MS method. First, the method was developed and optimized using the etanercept monomer. Conditions including MS parameters, flow rate, and gradient were investigated. Then, the developed method was used to analyze a new recombinant vaccine, protein 1. Similar to the etanercept monomer, the intact molecular information of protein 1, which cannot be obtained by RPLC-MS and SEC-MS, can be achieved using SCX-MS. Combined with information obtained on peptide mapping and glycan profiles obtained by LC-MS, the new vaccine was well characterized. Finally, the SCX-MS method was used to quickly evaluate the batch-to-batch reproducibility of protein 1. It was much faster than peptide mapping and glycan profiling methods and can provide information complementary to these strategies. It should be useful for many applications where speed and comprehensive characterization are required, such as recombinant sialylated vaccines and fusion proteins.

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Synthetic Leaves Based on Crystalline Olefin-Linked Covalent Organic Frameworks for Efficient CO2 Photoreduction with Water.

We report, for the first time, a new synthetic strategy for the preparation of crystalline two-dimensional olefin-linked covalent organic frameworks (COFs) based on aldol condensation between benzodifurandione and aromatic aldehydes. Olefin-linked COFs can be facilely crystallized through either a pyridine-promoted solvothermal process or a benzoic anhydride-mediated organic flux synthesis. The resultant COF leaf with high in-plane π-conjugation exhibits efficient visible-light-driven photoreduction of carbon dioxide (CO2) with water (H2O) in the absence of any photosensitizer, sacrificial agents, or cocatalysts. The production rate of carbon monoxide (CO) reaches as high as 158.1 µmol g-1 h-1 with near 100% CO selectivity, which is accompanied by the oxidation of H2O to oxygen. Both theoretical and experimental results confirm that the key lies in achieving exceptional photoinduced charge separation and low exciton binding. We anticipate that our findings will facilitate new possibilities for the development of semiconducting COFs with structural diversity and functional variability.

A challenging case of drug-related acute fibrinous and organizing pneumonia: A rare case report.

A 65-year-old man presented with intermittent fever and progressive shortness of breath. He responded poorly to antibiotics and corticosteroids (methylprednisolone 40 mg/d). Chest computed tomography scans showed diffuse consolidations and ground glass density patchy opacities in both lungs and these lesions progressed rapidly. The diagnosis of acute fibrinous and organizing pneumonia (AFOP) was confirmed through transbronchial cryobiopsy. This patient had prostate cancer with bone metastasis for 4 months and took the anti-prostate cancer medications including apalutamide and leuprorelin acetate. Considering his medication history, the patient was diagnosed with AFOP induced by anti-prostate cancer medications through panel discussion of multidisciplinary teams. Intravenous methylprednisolone of 500 mg/day was administered for 3 days and then slowly tapered. The patient's shortness of breath gradually subsided. In addition, the lesions in the lungs improved significantly on follow up imaging. AFOP induced by anti-prostate cancer medications is rare. To our knowledge, this is the first reported case and high-dose glucocorticoid treatment may be required in some of these cases.

Artificial kagome lattices of Shockley surface states patterned by halogen hydrogen-bonded organic frameworks.

Artificial electronic kagome lattices may emerge from electronic potential landscapes using customized structures with exotic supersymmetries, benefiting from the confinement of Shockley surface-state electrons on coinage metals, which offers a flexible approach to realizing intriguing quantum phases of matter that are highly desired but scarce in available kagome materials. Here, we devise a general strategy to construct varieties of electronic kagome lattices by utilizing the on-surface synthesis of halogen hydrogen-bonded organic frameworks (XHOFs). As a proof of concept, we demonstrate three XHOFs on Ag(111) and Au(111) surfaces, which correspondingly deliver regular, breathing, and chiral breathing diatomic-kagome lattices with patterned potential landscapes, showing evident topological edge states at the interfaces. The combination of scanning tunnelling microscopy and noncontact atomic force microscopy, complemented by density functional theory and tight-binding calculations, directly substantiates our method as a reliable and effective way to achieve electronic kagome lattices for engineering quantum states.

Study on the Design, Synthesis, Bioactivity and Translocation of the Conjugates of Phenazine-1-carboxylic Acid and N-Phenyl Alanine Ester.

The natural pesticide phenazine-1-carboxylic acid (PCA) is known to lack phloem mobility, whereas Metalaxyl is a representative phloem systemic fungicide. In order to endow PCA with phloem mobility and also enhance its antifungal activity, thirty-two phenazine-1-carboxylic acid-N-phenylalanine esters conjugates were designed and synthesized by conjugating PCA with the active structure N-acylalanine methyl ester of Metalaxyl. All target compounds were characterized by 1H NMR, 13C NMR and HRMS. The antifungal evaluation results revealed that several target compounds exhibited moderate to potent antifungal activities against Sclerotinia sclerotiorum, Bipolaris sorokiniana, Phytophthora parasitica, Phytophthora citrophthora. In particular, compound F7 displayed excellent antifungal activity against S. sclerotiorum with an EC50 value of 6.57 µg/mL, which was superior to that of Metalaxyl. Phloem mobility study in castor bean system indicated good phloem mobility for the target compounds F1-F16. Particularly, compound F2 exhibited excellent phloem mobility; the content of compound F2 in the phloem sap of castor bean was 19.12 µmol/L, which was six times higher than Metalaxyl (3.56 µmol/L). The phloem mobility tests under different pH culture solutions verified the phloem translocation of compounds related to the "ion trap" effect. The distribution of the compound F2 in tobacco plants further suggested its ambimobility in the phloem, exhibiting directional accumulation towards the apical growth point and the root. These results provide valuable insights for developing phloem mobility fungicides mediated by exogenous compounds.

Mixed crushing and competitive leaching of all electrode material components and metal collector fluid in the spent lithium battery.

Hydrometallurgy is a primary method for recovering cathode electrode materials from spent lithium-ion batteries (LIBs). Most of the current research materials are pure cathode electrode materials obtained through manual disassembly. However, the spent LIBs are typically broken as a whole during the actual industrial recycling which makes the electrode materials combined with the collector fluid. Therefore, the competitive leaching between metal collector fluid and electrode material was examined. The pyrolysis characteristics of the electrode materials were analyzed to determine the pyrolysis temperature. The electrode sheet was pyrolyzed and then crushed for competitive leaching. The effect of pyrolysis was analyzed by XPS. The competitive leaching behavior was studied based on leaching agent concentration, leaching time and leaching temperature. The composition and morphology of the residue were determined to prove the competitive leaching results by XRD-SEM. TG results showed that 500 °C was the suitable pyrolysis temperature. XPS analysis demonstrated that pyrolysis can completely remove PVDF. Li and Co were preferentially leached during the competitive leaching while the leaching rates were 90.10% and 93.40% with 50 min leaching at 70 °C. The Al and Cu had weak competitive leachability and the leaching rate was 29.10% and 0.00%. XRD-SEM analysis showed that Li and Co can be fully leached with residual Al and Cu remaining. The results showed that the mixed leaching of electrode materials is feasible based on its excellent selective leaching properties.

Whole-transcriptome profiling reveals potential biomarkers for the reversal of thymic epithelial cell senescence by umbilical cord mesenchymal stem cells.

BACKGROUND: Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) reverse the structure and function of the senescent thymus in vivo. However, the transcriptomic regulation mechanism is unclear. METHODS: TECs were cultured with H2O2 for 72 hours to induce senescence. UCMSCs were cocultured with senescent TECs for 48 hours to detect SA-ß-gal, P16 and Ki67. The cocultured TECs were collected for lncRNA, mRNA and miRNA sequencing to establish a competitive endogenous regulatory network (ceRNA). And RT-qPCR, immunofluorescence staining, and western blot were used to identified key genes. RESULTS: Our results showed that H2O2 induced TEC aging and that UCMSCs reversed these changes. Compared with those in aged TECs, 2260 DE mRNAs, 1033 DE lncRNAs and 67 DE miRNAs were differentially expressed, and these changes were reversed by coculturing the cells with UCMSCs. Differential mRNA enrichment analysis of ceRNA regulation revealed that the PI3K-AKT pathway was a significant signaling pathway. UCMSC coculture upregulated VEGFA, which is the upstream factor of the PI3K-AKT signaling pathway, and the expression of the key proteins PI3K and AKT. Thus, the expression of the cell cycle suppressor P27, which is downstream of the PI3K-AKT signaling pathway, was downregulated, while the expression of the cell cycle regulators CDK2 and CCNE was upregulated. CONCLUSION: UCMSC coculture upregulated the expression of VEGFA, activated the PI3K-AKT signaling pathway, increased the expression of CDK2 and CCNE, decreased the expression of P27, and promoted the proliferation of TECs.

Molecular characteristics and multivariate survival analysis of 43 patients with locally advanced or metastatic esophageal squamous cell carcinoma.

Background: Esophageal cancer (EC) is an aggressive malignant tumor with poor prognosis and high incidence. It is the sixth leading cause of cancer-related death in the world, and the 5-year overall survival (OS) rate is only 12-20%. The rapid development of next-generation sequencing (NGS) has provided powerful help for the treatment and management of EC patients. Methods: Tumor tissue and blood samples of 43 Chinese patients with nonsurgical esophageal squamous cell carcinoma (ESCC) were sequenced using a 425 gene-panel. Genomic profiling was explored and and the Cox proportional hazards model was used to analyze the correlations between gene or signaling pathway alterations and prognosis. Results: In this study, the most common mutated genes were TP53 (90.5%), CCND1 (45.2%), FGF19 (38.1%), NOTCH1 (26.2%), PI3KCA (21.4%) and CDKN2A (19%). Among these mutations, PI3KCA and NOTCH1 showed mutual exclusion to some extent. In the univariate model, mutations in NOTCH1, CBLB and TSC2 genes and tumor mutation burden (TMB) ≥7 were independent biomarkers of OS. NOTCH1 (P=0.007, HR =2.87), CBLB (P=0.011, HR =4.68) and TSC2 (P=0.024, HR =3.7) were significantly associated with poorer OS, and patients with TMB ≥7 had longer OS (P=0.151, HR =0.31). In addition, patients who carried alteration in NOTCH signaling pathway had reduced OS (P=0.014, HR =2.54). Conclusions: NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

Preparation of Aminated Sodium Lignosulfonate and Efficient Adsorption of Methyl Blue Dye.

The aminated sodium lignosulfonate (AELS) was prepared through a Mannich reaction and characterized via FT-IR, TG, SEM and XPS in this study. Subsequently, the adsorption capacity of AELS for methyl blue (MB) was evaluated under various conditions such as pH, adsorbent dosage, contact time, initial concentration and temperature. The adsorption kinetics, isotherms and thermodynamics of AELS for methyl blue were investigated and analyzed. The results were found to closely adhere to the pseudo-second-order kinetic model and Langmuir isotherm model, suggesting a single-molecular-layer adsorption process. Notably, the maximum adsorption capacity of AELS for methyl blue (153.42 mg g-1) was achieved under the specified conditions (T = 298 K, MAELS = 0.01 g, pH = 6, VMB = 25 mL, C0 = 300 mg L-1). The adsorption process was determined to be spontaneous and endothermic. Following five adsorption cycles, the adsorption capacity exhibited a minimal reduction from 118.99 mg g-1 to 114.33 mg g-1, indicating good stability. This study contributes to the advancement of utilizing natural resources effectively and sustainably.

Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.

Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

Multiomic study of the protective mechanism of Persicaria capitata (Buch.-Ham. ex D.Don) H.Gross against streptozotocin-induced diabetic nephropathy in Guizhou miniature pigs.

BACKGROUND: Persicaria capitata (Buch.-Ham. ex D.Don) H.Gross (P. capitata, PCB), a traditional drug of the Miao people in China, is potential traditional drug used for the treatment of diabetic nephropathy (DN). PURPOSE: The purpose of this study is to investigate the function of P. capitata and clarify its protective mechanism against DN. METHODS: We induced DN in the Guizhou miniature pig with injections of streptozotocin, and P. capitata was added to the pigs' diet to treat DN. In week 16, all the animals were slaughtered, samples were collected, and the relative DN indices were measured. 16S rRNA sequencing, metagenomics, metabolomics, RNA sequencing, and proteomics were used to explore the protective mechanism of P. capitata against DN. RESULTS: Dietary supplementation with P. capitata significantly reduced the extent of the disease, not only in term of the relative disease indices but also in hematoxylin-eosin-stained tissues. A multiomic analysis showed that two microbes (Clostridium baratii and Escherichia coli), five metabolites (oleic acid, linoleic acid, 4-phenylbutyric acid, 18-ß-glycyrrhetinic acid, and ergosterol peroxide), four proteins (ENTPD5, EPHX1, ARVCF and TREH), four important mRNAs (encoding ENTPD5, EPHX1, ARVCF, and TREH), six lncRNAs (TCONS_00024194, TCONS_00085825, TCONS_00006937, TCONS_00070981, TCONS_00074099, and TCONS_00097913), and two circRNAs (novel_circ_0001514 and novel_circ_0017507) are all involved in the protective mechanism of P. capitata against DN. CONCLUSIONS: Our results provide multidimensional theoretical support for the study and application of P. capitata.

Using the Super Learner algorithm to predict risk of major adverse cardiovascular events after percutaneous coronary intervention in patients with myocardial infarction.

BACKGROUND: The primary treatment for patients with myocardial infarction (MI) is percutaneous coronary intervention (PCI). Despite this, the incidence of major adverse cardiovascular events (MACEs) remains a significant concern. Our study seeks to optimize PCI predictive modeling by employing an ensemble learning approach to identify the most effective combination of predictive variables. METHODS AND RESULTS: We conducted a retrospective, non-interventional analysis of MI patient data from 2018 to 2021, focusing on those who underwent PCI. Our principal metric was the occurrence of 1-year postoperative MACEs. Variable selection was performed using lasso regression, and predictive models were developed using the Super Learner (SL) algorithm. Model performance was appraised by the area under the receiver operating characteristic curve (AUC) and the average precision (AP) score. Our cohort included 3,880 PCI patients, with 475 (12.2%) experiencing MACEs within one year. The SL model exhibited superior discriminative performance, achieving a validated AUC of 0.982 and an AP of 0.971, which markedly surpassed the traditional logistic regression models (AUC: 0.826, AP: 0.626) in the test cohort. Thirteen variables were significantly associated with the occurrence of 1-year MACEs. CONCLUSION: Implementing the Super Learner algorithm has substantially enhanced the predictive accuracy for the risk of MACEs in MI patients. This advancement presents a promising tool for clinicians to craft individualized, data-driven interventions to better patient outcomes.