Identification of vitamin D-related signature for predicting the clinical outcome and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers globally, seriously endangering people health. Vitamin D was significantly associated with tumor progression and patients' prognosis. Integrative 10 machine learning algorithms were used to develop a Vitamin D-related signature (VRS) with one training cohort and 3 testing cohorts. The performance of VRS in predicting the immunology response was verified using several predicting approaches. The optimal VRS was constructed by stepCox + superPC algorithm. VRS acted as a risk factor for HCC patients. HCC patients with high-risk score had a poor clinical outcome and the AUCs of 1-, 3-, and 5-year ROC were 0.786, 0.755, and 0.786, respectively. A higher level of CD8 + cytotoxic T cells and B cells was obtained in HCC patients with low-risk score. There is higher PD1&CTLA4 immunophenoscore and TMB score in low-risk score in HCC patients. Lower TIDE score and tumor escape score was found in HCC cases with low-risk score. The IC50 value of camptothecin, docetaxel, crizotinib, dasatinib, and erlotinib was lower in HCC cases with high-risk score. HCC patients with high-risk score had a higher score of cancer-related hallmarks, including angiogenesis, glycolysis, and NOTCH signaling. Our study proposed a novel VRS for HCC, which served as an indicator for predicting clinical outcome and immunotherapy responses in HCC.

Establishing national reference materials for genetic testing of cytochrome P450.

OBJECTIVES: Reference materials for in-vitro diagnostic reagents play a critical role in determining the quality of reagents and ensuring the accuracy of clinical test results. This study aimed to establish a national reference material (NRM) for detecting cytochrome P450 (CYP) genes related to drug metabolism by screening databases on the Chinese population to identify CYP gene polymorphism characteristics. METHODS: To prepare the NRM, we used DNA extracted from healthy human immortalized B lymphoblastoid cell lines as the raw material. Samples of these cell lines were obtained from the Chinese Population PGx Gene Polymorphism Biobank. Further, we used Sanger sequencing, next-generation sequencing, and commercial assay kits to validate the polymorphic genotypes. RESULTS: Among the CYP superfamily genes, we confirmed 24 riboswitch loci related to drug metabolism, with evidence levels of 1A, 2A, 3, and 4. We confirmed the polymorphic loci and validated their genotypes using various sequencing techniques. Our results were consistent with the polymorphism information of samples obtained from the biobank, thus demonstrating high precision and stability of the established NRM. CONCLUSION: An NRM (360 056-202 201) for CYP genetic testing covering 24 loci related to drug metabolism was established and approved to assess in-vitro diagnostic reagents containing CYP family gene polymorphisms and perform clinical inter-room quality evaluations.

Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling.

OBJECTIVE: Obesity is a global health concern with management strategies encompassing bariatric surgery and anti-obesity drugs; however, concerns regarding complexities and side effects persist, driving research for more effective, low-risk strategies. The promotion of white adipose tissue (WAT) browning has emerged as a promising approach. Moreover, alisol B 23-acetate (AB23A) has demonstrated efficacy in addressing metabolic disorders, suggesting its potential as a therapeutic agent in obesity management. Therefore, in this study, we aimed to investigate the therapeutic potential of AB23A for mitigating obesity by regulating metabolic phenotypes and lipid distribution in mice fed a high-fat diet (HFD). METHODS: An obesity mouse model was established by administration of an HFD. Glucose and insulin metabolism were assessed via glucose and insulin tolerance tests. Adipocyte size was determined using hematoxylin and eosin staining. The expression of browning markers in WAT was evaluated using Western blotting and quantitative real-time polymerase chain reaction. Metabolic cage monitoring involved the assessment of various parameters, including food and water intake, energy metabolism, respiratory exchange rates, and physical activity. Moreover, oil red O staining was used to evaluate intracellular lipid accumulation. A bioinformatic analysis tool for identifying the molecular mechanisms of traditional Chinese medicine was used to examine AB23A targets and associated signaling pathways. RESULTS: AB23A administration significantly reduced the weight of obese mice, decreased the mass of inguinal WAT, epididymal WAT, and perirenal adipose tissue, improved glucose and insulin metabolism, and reduced adipocyte size. Moreover, treatment with AB23A promoted the expression of browning markers in WAT, enhanced overall energy metabolism in mice, and had no discernible effect on food intake, water consumption, or physical activity. In 3T3-L1 cells, AB23A inhibited lipid accumulation, and both AB23A and rapamycin inhibited the mammalian target of rapamycin-sterol regulatory element-binding protein-1 (mTOR-SREBP1) signaling pathway. Furthermore, 3-isobutyl-1-methylxanthine, dexamethasone and insulin, at concentrations of 0.25 mmol/L, 0.25 µmol/L and 1 µg/mL, respectively, induced activation of the mTOR-SREBP1 signaling pathway, which was further strengthened by an mTOR activator MHY1485. Notably, MHY1485 reversed the beneficial effects of AB23A in 3T3-L1 cells. CONCLUSION: AB23A promoted WAT browning by inhibiting the mTOR-SREBP1 signaling pathway, offering a potential strategy to prevent obesity. Please cite this article as: Han LL, Zhang X, Zhang H, Li T, Zhao YC, Tian MH, Sun FL, Feng B. Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling. J Integr Med. 2024; 22(1): 83-92.

Urinary exosomal microRNA-145-5p and microRNA-27a-3p act as noninvasive diagnostic biomarkers for diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD), characterized by increased urinary microalbumin levels and decreased renal function, is the primary cause of end-stage renal disease. Its pathological mechanisms are complicated and multifactorial; Therefore, sensitive and specific biomarkers are needed. Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney. The microRNAs (miRNAs) in urinary exosome are remarkably stable and highly tissue-specific for the kidney. AIM: To determine if urinary exosomal miRNAs from diabetic patients can serve as noninvasive biomarkers for early DKD diagnosis. METHODS: Type 2 diabetic mellitus (T2DM) patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups: DM, diabetic patients without albuminuria [urinary albumin to creatinine ratio (UACR) < 30 mg/g] and DKD, diabetic patients with albuminuria (UACR ≥ 30 mg/g). Healthy subjects were the normal control (NC) group. Urinary exosomal miR-145-5p, miR-27a-3p, and miR-29c-3p, were detected using real-time quantitative polymerase chain reaction. The correlation between exosomal miRNAs and the clinical indexes was evaluated. The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic (ROC) analysis. Biological functions of miR-145-5p were investigated by performing Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. RESULTS: Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group (miR-145-5p: 4.54 ± 1.45 vs 1.95 ± 0.93, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.71 ± 0.76, P < 0.05) and the NC group (miR-145-5p: 4.54 ± 1.45 vs 1.55 ± 0.83, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.10 ± 0.51, P < 0.001). The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate. miR-27a-3p was also closely related to blood glucose, glycosylated hemoglobin A1c, and low-density lipoprotein cholesterol. ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88 [95% confidence interval (CI): 0.784-0.985, P < 0.0001] in diagnosing DKD than miR-27a-3p with 0.71 (95%CI: 0.547-0.871, P = 0.0239). Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament, cytoskeleton, and extracellular exosome and were involved in the pathological processes of DKD, including apoptosis, inflammation, and fibrosis. CONCLUSION: Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.

Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression.

OBJECTIVE: Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression. How neutrophils promote lung cancer progression, however, has not been established. METHODS: Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients. The effect of neutrophils on lung cancer was determined using the Transwell migration assay, a proliferation assay, and a murine tumor model. Gene knockdown was used to determine poly ADP-ribose polymerase (PARP)-1 function in lung cancer-educated neutrophils. Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9 (MMP-9). Immunoprecipitation coupled to mass spectrometry (IP/MS) was used to identify the proteins interacting with PARP-1. Co-immunoprecipitation (Co-IP) was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase (ALOX5). Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression. RESULTS: An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients (P < 0.001). Neutrophil activation promoted lung cancer cell invasion, migration, and proliferation in vitro, and murine lung cancer growth in vivo. Mechanistically, PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification (PARylation). Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production, and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth. CONCLUSIONS: We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression, which exacerbates lung cancer progression.

A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer's disease.

Toxic amyloid-beta (Aß) plaque and harmful inflammation are two leading symptoms of Alzheimer's disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aß fibrils formation, degrades Aß fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.

Resolving Quantum Interference Black Box through Attosecond Photoionization Spectroscopy.

Multiphoton light-matter interactions invoke a so-called "black box" in which the experimental observations contain the quantum interference between multiple pathways. Here, we employ polarization-controlled attosecond photoelectron metrology with a partial wave manipulator to deduce the pathway interference within this quantum 'black box" for the two-photon ionization of neon atoms. The angle-dependent and attosecond time-resolved photoelectron spectra are measured across a broad energy range. Two-photon phase shifts for each partial wave are reconstructed through the comprehensive analysis of these photoelectron spectra. We resolve the quantum interference between the degenerate p→d→p and p→s→p two-photon ionization pathways, in agreement with our theoretical simulations. Our approach thus provides an attosecond time-resolved microscope to look inside the "black box" of pathway interference in ultrafast dynamics of atoms, molecules, and condensed matter.

Urinary exosomes from patients with diabetic kidney disease induced podocyte apoptosis via microRNA-145-5p/Srgap2 and the RhoA/ROCK pathway.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease without early diagnostic and specific therapeutic approaches. Podocyte apoptosis and loss play important roles in the pathological process of DKD. This study aimed to explore whether urinary exosomes from type 2 diabetes patients with DKD could induce podocyte apoptosis and the underlying pathological mechanisms. The exosomes were isolated from the urine samples of patients with DKD (DKD-Exo). Later, they were taken up and internalized by MPC5 cells. MPC5 cells were co-cultured with DKD-Exo (45 µg/ml) for 24 h in the presence or absence of microRNA-145-5p (miR-145-5p) inhibitor, fasudil and pcDNA-Srgap2 transfection. MiR-145-5p and Srgap2 expression was evaluated using real-time quantitative PCR. The protein levels of Srgap2, Bcl-2, Bax, and cleaved caspase-3, as well as ROCK activity were determined using Western blotting. Cell apoptosis was measured using flow cytometry and the TUNEL assay. miR-145-5p expression in MPC5 cells exposed to DKD-Exo was markedly upregulated. miR-145-5p negatively regulated Srgap2 levels. Exposure of MPC5 cells to DKD-Exo reduced Srgap2 expression and activated ROCK, which was partly reversed by the presence of the miR-145-5p inhibitor or Srgap2 overexpression. The apoptosis of MPC5 cells exposed to DKD-Exo increased significantly, which was counteracted by the addition of the miR-145-5p inhibitor and fasudil. The results showed that urinary exosomal miR-145-5p from patients with DKD induced podocyte apoptosis by inhibiting Srgap2 and activating the RhoA/ROCK pathway, suggesting that urinary exosomal miR-145-5p is involved in the pathological process of DKD and could become a noninvasive diagnostic biomarker for DKD.

Exosomal microRNAs: potential nanotherapeutic targets for diabetic kidney disease.

Diabetic kidney disease (DKD) is a primary cause for end-stage renal disease, but no specific therapeutic approaches exist. Exosomal miRNAs, a key functional cargo of nanovesicles, play crucial roles in the pathophysiological processes of DKD. Exosomal miRNAs are involved in cell-to-cell transfer of biological information, mediating nephritic inflammation, oxidative stress, apoptosis, autophagy, epithelial-mesenchymal transition and fibrosis. Circulating exosomal miRNAs derived from urine or serum might function as noninvasive prognostic biomarkers for DKD. Exosomal miRNAs from stem cells have been reported to exert beneficial effects on diabetic kidneys, which suggests that these exosomes might function as potential nanotherapy tools for treating DKD. In this review, we have summarized recent studies based on the association between exosomal miRNAs and DKD.

Counterintuitive relationship between the triglyceride glucose index and diabetic foot in diabetes patients: A cross-sectional study.

BACKGROUND: Research has shown that insulin resistance (IR) is a known risk factor for diabetic foot (DF), and the triglyceride-glucose (TyG) index is a reliable and simple indicator of IR. However, less is known about the relationship between the TyG and the risk of DF. Here, we investigated the association between the TyG index and the prevalence of DF. METHODS: The eligible records from the Departments of Endocrinology of Shandong Provincial Hospital Affiliated to Shandong First Medical University were screened (from December 1, 2012, to December 31, 2021), and a total of 8866 patients were enrolled. The TyG index was calculated as ln[(fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2)]. The continuous variables between the DF and the non-DF groups were compared by Student's t test or the Mann-Whitney U test, and categorical variables were compared by the chi-square test. Receiver operating characteristic curve (ROC) analysis was carried out to estimate the predictive value of the TyG index for DF. Logistic regression models were used to evaluate the associations between the quartiles of the TyG index and the risk of DF. Subgroup and sensitivity analyses were conducted. RESULTS: The TyG index was significantly lower in the DF group than in the no-DF group. The logistic regression revealed that an increased TyG index was associated with a lower risk of DF after adjusting for potential confounders. In addition, an ROC analysis indicated the discriminatory ability of the TyG index in DF presence with an area under the curve (AUC) of 0.661 (95% CI 0.642-0.680, P < 0.001). Subgroup and sensitivity analysis also supported these robust results. CONCLUSIONS: The TyG index was inversely and dose-dependently associated with the risk of DF in diabetes patients, indicating that elevated TyG index was a protective factor for DF. Future studies are therefore warranted to confirm our finding and to explore the detailed pathological mechanism involved in this process.

Yeast Peptides Improve the Intestinal Barrier Function and Alleviate Weaning Stress by Changing the Intestinal Microflora Structure of Weaned Lambs.

Early weaning stress in lambs leads to decreased feed intake, damage to intestinal morphology, changes in the microbial flora structure, and subsequent complications. Yeast peptides are antimicrobial peptides with anti-inflammatory, antioxidant, and bacteriostasis effects. To study the effects of yeast peptides on relieving weaning stress in lambs, 54 lambs were randomly divided into three groups: ewe-reared (ER), yeast-peptide-treated (AP), and early-weaned (EW) lambs. The body weight and dry matter intake did not significantly differ among all groups. After weaning, the daily gain and feed conversion rate decreased significantly (p < 0.01), but AP showed an upward trend. In the EW group, immunoglobulin (Ig) levels changed significantly post-weaning (IgG decreased; IgA and IgM increased); the villi shortened, the crypt depth increased, and the villi height/crypt depth decreased (p < 0.001). The abundance and diversity of microflora among all groups were not significantly different. A column coordinate analysis showed significant differences in the intestinal microbial structure between the AP and EW groups. Lactobacillus, Aeriscardovia, Ruminosaceae_UCG-014, and Catenisphaera may play key roles in alleviating weaning stress in lambs. Our study provides new clues for alleviating weaning stress in lambs by describing the influence of yeast peptides on the intestinal microflora during weaning.

Identifying photoelectron releasing order in strong-field dissociative ionization of H2.

Driven by intense laser fields, the outgoing photoelectrons in molecules possess a quiver motion, resulting in the rise of the effective ionization potential. The coupling of the field-dressed ionization potential with abundant molecular dynamics complicates the laser-molecule interactions. Here, we demonstrate an approach to resolve photoelectron releasing order in the dissociative and non-dissociative channels of multiphoton ionization driven by an orthogonally polarized two-color femtosecond laser pulse. The photoelectron kinetic energy releases and the regular nodes in the photoelectron angular distributions due to the participation of different continuum partial waves allow us to deduce the field-dressed ionization potential of various channels. It returns the ponderomotive energy experienced by the outgoing electron and reveals the corresponding photoionization instants within the laser pulse. Our results provide a route to explore the complex strong-field ionization dynamics of molecules using two-dimensional photoelectron momentum spectroscopy.

An overview of systematic reviews of acupuncture for diabetic gastroparesis.

Background: To date, several systematic reviews and/or meta-analyses (SRs/MAs) on the topic of acupuncture as a treatment for diabetic gastroparesis (DGP) have been published. However, whether acupuncture is an effective and safe treatment for DGP remains controversial. In this study, we aimed to determine whether the methodology and results of previously published SRs/MAs of acupuncture as a treatment for DGP were of sufficient quality to be considered reliable. Methods: We extensively searched seven databases, including PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge, Wan Fang, and Chongqing VIP, for SRs/MAs published before or on September 16, 2022. The SRs/MAs that met the inclusion criteria were evaluated for the quality of the methodology and results using the Assessing the Methodological Quality of Systematic Reviews Two (AMSTAR-2) and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tools. A re-meta-analysis of primary outcome indicators was also performed. Results: Ten SRs/MAs that met the inclusion criteria were obtained. Using the AMSTAR-2, which is a methodological quality assessment tool, two MAs were rated as low quality, and eight SRs/MAs were rated as extremely low quality. Assessment with the GRADE tool revealed that, among 20 results, 4 were of moderate quality, 10 were of low quality, and 6 were of very low quality. Re-meta-analysis of primary outcome indicators revealed that, in terms of total efficiency, all types of acupuncture interventions, such as acupuncture, electroacupuncture, and acupoint injection, performed better than the controls, such as gastroprokinetic agents and sham acupuncture. Moreover, in the treatment of DGP, acupuncture exhibited fewer side effects compared to the controls. Conclusion: Acupuncture appears to improve the symptoms of patients with DGP, and the side effects of acupuncture as a treatment for DGP are inferior to those of the controls. However, owing to the low quality of the methodology and results of the SRs/MAs, these findings cannot be considered reliable and need to be validated by additional studies with rigorous standards of experimental design and protocols and larger sample sizes.

Dual-Site Förster Resonance Energy Transfer Route of Upconversion Nanoparticles-Based Brain-Targeted Nanotheranostic Boosts the Near-Infrared Phototherapy of Glioma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with low survival, primarily due to the blood-brain barrier (BBB) and high infiltration. Upconversion nanoparticles (UCNPs)-based near-infrared (NIR) phototherapy with deep penetration is a promising therapy method against glioma but faces low photoenergy utilization that is induced by spectral mismatch and single-site Förster resonance energy transfer (FRET). Herein, we designed a brain-targeting NIR theranostic system with a dual-site FRET route and superior spectral matching to maximize energy utilization for synergistic photodynamic and photothermal therapy of glioma. The system was fabricated by Tm-doped UCNPs, zinc tetraphenylporphyrin (ZnTPP), and copper sulfide (CuS) nanoparticles under multioptimized modulation. First, the Tm-doping ratio was precisely adjusted to improve the relative emission intensity at 475 nm of UCNPs (11.5-fold). Moreover, the J-aggregate of ZnTPP increased the absorption at 475 nm (163.5-fold) of monomer; both together optimize the FRET matching between UCNPs and porphyrin for effective NIR photodynamic therapy. Simultaneously, the emission at 800 nm was utilized to magnify the photothermal effect of CuS nanoparticles for photothermal therapy via the second FRET route. After being modified by a brain-targeted peptide, the system efficiently triggers the synergistic phototherapy ablation of glioma cells and significantly prolongs the survival of orthotopic glioma-bearing mice after traversing the BBB and targeting glioma. This success of advanced spectral modulation and dual-site FRET strategy may inspire more strategies to maximize the photoenergy utilization of UCNPs for brain diseases.

An oral polyphenol host-guest nanoparticle for targeted therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a global public health challenge that affects millions of people. Current medical treatments for IBD are not fully effective and may cause undesirable side effects on patients. Thus, there is an urgent need for safe, simple, and efficacious strategies to treat IBD in clinical settings. Here, we develop an oral polyphenol nanoparticle (PDT) by assembling dexamethasone sodium phosphate (DSP)-loaded poly-ß-cyclodextrin with tannic acid via host-guest interactions for treating IBD. This one-step assembly process is rapid (within 10 s), reproducible, and free of harmful chemical agents, which can facilitate its clinical translation. PDT is negatively charged due to the three components, which enable it to specifically target the positively charged inflamed colonic mucosa through electrostatic attraction, thus localizing the drug at the inflamed site to reduce systemic exposure and side effects. Furthermore, PDT exhibits a strong reactive oxygen species (ROS)-scavenging ability derived from the tannic acid component, which can alleviate ROS-mediated inflammatory responses and ameliorate IBD symptoms. Compared with free DSP, PDT demonstrates sustained DSP release behavior in vitro and in vivo, as well as enhanced therapeutic efficacy in a colitis mouse model. These results suggest that PDT might be a potential therapeutic agent for the treatment of IBD. Moreover, this facile polyphenol host-guest assembly strategy may provide a promising drug-delivery platform for treating various diseases STATEMENT OF SIGNIFICANCE: To develop safe and effective treatments for inflammatory bowel disease (IBD), we have designed an oral polyphenol nanoparticle (PDT) using the host-guest assembly of dexamethasone sodium phosphate (DSP)-loaded poly-ß-cyclodextrin with tannic acid. Through in vitro and in vivo experiments, PDT has demonstrated remarkable inflammation-targeting, ROS-scavenging, and anti-inflammatory properties, along with sustained release of DSP. Moreover, in an IBD mouse model, PDT has shown significantly improved therapeutic efficacy compared to free DSP. The host-guest assembly strategy employed for PDT is noteworthy for its rapidity, reproducibility, and safety due to the absence of harmful chemicals, holding great promise for designing a diverse range of nanomedicines customized for treating various diseases.

A roadmap for developing Venezuelan equine encephalitis virus (VEEV) vaccines: Lessons from the past, strategies for the future.

Venezuelan equine encephalitis (VEE) is a zoonotic infectious disease caused by the Venezuelan equine encephalitis virus (VEEV), which can lead to severe central nervous system infections in both humans and animals. At present, the medical community does not possess a viable means of addressing VEE, rendering the prevention of the virus a matter of paramount importance. Regarding the prevention and control of VEEV, the implementation of a vaccination program has been recognized as the most efficient strategy. Nevertheless, there are currently no licensed vaccines or drugs available for human use against VEEV. This imperative has led to a surge of interest in vaccine research, with VEEV being a prime focus for researchers in the field. In this paper, we initially present a comprehensive overview of the current taxonomic classification of VEEV and the cellular infection mechanism of the virus. Subsequently, we provide a detailed introduction of the prominent VEEV vaccine types presently available, including inactivated vaccines, live attenuated vaccines, nucleic acid, and virus-like particle vaccines. Moreover, we emphasize the challenges that current VEEV vaccine development faces and suggest urgent measures that must be taken to overcome these obstacles. Notably, based on our latest research, we propose the feasibility of incorporation codon usage bias strategies to create the novel VEEV vaccine. Finally, we prose several areas that future VEEV vaccine development should focus on. Our objective is to encourage collaboration between the medical and veterinary communities, expedite the translation of existing vaccines from laboratory to clinical applications, while also preparing for future outbreaks of new VEEV variants.

Changes of Serum Bone Metabolism Indexes and Ultrasonic Bone Mineral Density in Patients with Diabetic Nephropathy at Different Stages and their effects on Diabetic Renal Microvascular Complications.

Objective: To determine the changes in serum bone metabolism indexes and ultrasonic bone mineral density (BMD) in patients with diabetic nephropathy at different stages, and their effects on diabetic renal microvascular complications. Methods: This is a clinical comparative study. One hundred twenty two diabetic patients admitted to the Baoding No.1 Central Hospital from January 2020 to March 2022 were selected as subjects and divided into three groups according to their actual condition: the simple diabetes (Group-A, 40 cases), diabetic nephropathy with micro urinary protein (Group-B, 40 cases) and diabetic nephropathy with massive proteinuria (Group-C, 42 cases). Another 36 healthy subjects were selected as the control group. Differences in serum bone metabolism indexes and ultrasound BMD levels were compared. Results: Twenty five hydroxy-vitamin D, BGP, T-PINP and ultrasound BMD levels in the control group were > Group-A > Group-B > Group-C, PTH and ß-CTX in the control group were < Group-A < Group-B < Group-C, statistically significant differences (p<0.05). The urinary albumin to urinary creatinine ratio (ACR) value in Group-B was significantly lower than Group-C (p<0.05). Logistic regression analysis showed that 25-hydroxy-vitamin D, PTH, BGP, ß-CTX, T-PINP and ultrasound BMD were the influencing factors of diabetic renal microvascular complications (p<0.05). Conclusion: Bone metabolism indexes and ultrasound bone mineral density are abnormally expressed in patients with diabetic nephropathy at different stages, which are closely related to the urine protein of patients. They have important clinical value in the diagnosis of early diabetic nephropathy.

A Brain-Targeting NIR-II Ferroptosis System: Effective Visualization and Oncotherapy for Orthotopic Glioblastoma.

Near-infrared-II (NIR-II) ferroptosis activators offer promising potentials in in vivo theranostics of deep tumors, such as glioma. However, most cases are nonvisual iron-based systems that are blind for in vivo precise theranostic study. Additionally, the iron species and their associated nonspecific activations might trigger undesired detrimental effects on normal cells. Considering gold (Au) is an essential cofactor for life and it can specifically bind to tumor cells, Au(I)-based NIR-II ferroptosis nanoparticles (TBTP-Au NPs) for brain-targeted orthotopic glioblastoma theranostics are innovatively constructed. It achieves the real-time visual monitoring of both the BBB penetration and the glioblastoma targeting processes. Moreover, it is first validated that the released TBTP-Au specifically activates the effective heme oxygenase-1-regulated ferroptosis of glioma cells to greatly extend the survival time of glioma-bearing mice. This new ferroptosis mechanism based on Au(I) may open a new way for the fabrication of advanced and high-specificity visual anticancer drugs for clinical trials.

B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis.

Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (ß2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-ß2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.