Drug-Loaded Mesoporous Silica Nanoparticles Enhance Antitumor Immunotherapy by Regulating MDSCs.

Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.

Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms.

PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

Regulation of IFP in solid tumours through acoustic pressure to enhance infiltration of nanoparticles of various sizes.

Numerous nanomedicines have been developed recently that can accumulate selectively in tumours due to the enhanced permeability and retention (EPR) effect. However, the high interstitial fluid pressure (IFP) in solid tumours limits the targeted delivery of nanomedicines. We were previously able to relieve intra-tumoural IFP by low-frequency non-focused ultrasound (LFNFU) through ultrasonic targeted microbubble destruction (UTMD), improving the targeted delivery of FITC-dextran. However, the accumulation of nanoparticles of different sizes and the optimal acoustic pressure were not evaluated. In this study, we synthesised Cy5.5-conjugated mesoporous silica nanoparticles (Cy5.5-MSNs) of different sizes using a one-pot method. The Cy5.5-MSNs exhibited excellent stability and biosafety regardless of size. MCF7 tumour-bearing mice were subjected to UTMD over a range of acoustic pressures (0.5, 0.8, 1.5 and 2.0 MPa), and injected intravenously with Cy5.5-MSNs. Blood perfusion, tumour IFP and intra-tumoural accumulation of Cy5.5-MSNs were analysed. Blood perfusion and IFP initially rose, and then declined, as acoustic pressure intensified. Furthermore, UTMD significantly enhanced the accumulation of differentially sized Cy5.5-MSNs in tumour tissues compared to that of the control group, and the increase was sevenfold higher at an acoustic pressure of 1.5 MPa. Taken together, UTMD enhanced the infiltration and accumulation of Cy5.5-MSNs of different sizes in solid tumours by reducing intra-tumour IFP.

Profiling cortical morphometric similarity in perinatal brains: Insights from development, sex difference, and inter-individual variation.

The topological organization of the macroscopic cortical networks important for the development of complex brain functions. However, how the cortical morphometric organization develops during the third trimester and whether it demonstrates sexual and individual differences at this particular stage remain unclear. Here, we constructed the morphometric similarity network (MSN) based on morphological and microstructural features derived from multimodal MRI of two independent cohorts (cross-sectional and longitudinal) scanned at 30-44 postmenstrual weeks (PMW). Sex difference and inter-individual variations of the MSN were also examined on these cohorts. The cross-sectional analysis revealed that both network integration and segregation changed in a nonlinear biphasic trajectory, which was supported by the results obtained from longitudinal analysis. The community structure showed remarkable consistency between bilateral hemispheres and maintained stability across PMWs. Connectivity within the primary cortex strengthened faster than that within high-order communities. Compared to females, male neonates showed a significant reduction in the participation coefficient within prefrontal and parietal cortices, while their overall network organization and community architecture remained comparable. Furthermore, by using the morphometric similarity as features, we achieved over 65 % accuracy in identifying an individual at term-equivalent age from images acquired after birth, and vice versa. These findings provide comprehensive insights into the development of morphometric similarity throughout the perinatal cortex, enhancing our understanding of the establishment of neuroanatomical organization during early life.

New piperazine and morpholine derivatives: Mass spectrometry characterization and evaluation of their antimicrobial activity.

Recently, pharmaceutical research has been focused on the design of new antibacterial drugs with higher selectivity towards several strains. Major issues concern the possibility to obtain compounds with fewer side effects, at the same time effectively overcoming the problem of antimicrobial resistance. Several solutions include the synthesis of new pharmacophores starting from piperazine or morpholine core units. Mass spectrometry-based techniques offer important support for the structural characterization of newly synthesized compounds to design safer and more effective drugs for various medical conditions. Here, two new piperazine derivatives and four new morpholine derivatives were synthesized and structurally characterized through a combined approach of Fourier transform-ion cyclotron resonance (FT-ICR) and Linear Trap Quadrupole (LTQ) mass spectrometry. The support of both high-resolution and low-resolution mass spectrometric data namely accurate mass measurements, isotopic distribution and MSn spectra, was crucial to confirm the success of the synthesis. These compounds were further evaluated for inhibitory activity against a total of twenty-nine Gram-positive and Gram-negative bacteria to determine the action spectrum and the antimicrobial effectiveness. Results demonstrated compounds' antimicrobial activity against many tested bacterial species, providing an inhibitory effect linked to different chemical structure and suggesting that the new-synthesized derivatives could be considered as promising antimicrobial agents.

In-Electrospray source Hydrogen/Deuterium exchange coupled to multistage fragmentation for the investigation of the protonation and fragmentation pathways of gas phase ions.

Identification of molecules in complex natural matrices relies on matching the fragmentation spectra of ions under investigation and the spectra acquired for the corresponding analytical standards. Currently, there are many databases of experimentally measured tandem mass spectrometry spectra (such as NIST, MzCloud, and Metlin), and considerable progress has been made in the development of software for predicting tandem mass spectrometry fragments in silico using combinatorial, machine learning, and quantum chemistry approaches (such as MetFrag, CFM-ID, and QCxMS). However, the electrospray ionization molecules can be ionized at different sites (protonated or deprotonated), and the fragmentation spectra of such ions are different. Here, we are using the combination of the in-ESI source hydrogen/deuterium exchange reaction and MSn fragmentation for the investigation of the fragmentation pathways for different protomers of organic molecules. It is shown that the distribution of the deuterium in the fragment ions reflects the presence of different protomers. For several molecules, the distribution of deuterium was traced up to the MS5 level of fragmentation revealing many unusual and unexpected effects. For example, we investigated the loss of HF from the ciprofloxacin and norfloxacin ions and observed that for ions protonated at -COOH group, the eliminating hydrogen always comes from -NH group. When ions are protonated at another site, the elimination of hydrogen with a probability of 30% occurs from the -NH group, and with a probability of 70%, it originates from other sites on the molecule. Such effects were not described previously. Quantum chemical simulation was used for the verification of the protonated structures and simulation of the corresponding fragmentation spectra.

Combined transcriptome and proteome analysis reveals MSN and ARFIP2 as biomarkers for trastuzumab resistance of breast cancer.

PURPOSE: HER2-positive breast cancer (BC) accounts for 20-30% of all BC subtypes and is linked to poor prognosis. Trastuzumab (Tz), a humanized anti-HER2 monoclonal antibody, is a first-line treatment for HER2-positive breast cancer which faces resistance challenges. This study aimed to identify the biomarkers driving trastuzumab resistance. METHODS: Differential expression analysis of genes and proteins between trastuzumab-sensitive (TS) and trastuzumab-resistant (TR) cells was conducted using RNA-seq and iTRAQ. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used to study their functions. The prognostic significance and protein levels of ARFIP2 and MSN were evaluated using online tools and immunohistochemistry. Sensitivity of MSN and ARFIP2 to other therapies was assessed using public pharmacogenomics databases and the R language. RESULTS: Five genes were up-regulated, and nine genes were down-regulated in TR cells at both transcriptional and protein levels. Low ARFIP2 and high MSN expression linked to poor BC prognosis. MSN increased and ARFIP2 decreased in TR patients, correlating with shorter OS. MSN negatively impacted fulvestrant and immunotherapy sensitivity, while ARFIP2 had a positive impact. CONCLUSION: Our findings suggest that MSN and ARFIP2 could serve as promising biomarkers for predicting response to Tz, offering valuable insights for future research in the identification of diagnostic and therapeutic targets for BC patients with Tz resistance.

ΔNp73 and its effector targets promote colorectal peritoneal carcinosis and predict survival.

Peritoneal metastasis of colorectal origin appears in ~10-15% of patients at the time of diagnosis and in 30-40% of cases with disease progression. Locoregional spread through the peritoneum is considered stage IVc and is associated with a poor prognosis. The development of a regional therapeutic strategy based on cytoreductive surgery, and hyperthermic intra-abdominal chemotherapy has significantly altered the course of the disease. Although recent evidence supports the benefits of cytoreductive surgery, the benefits of hyperthermic intra-abdominal chemotherapy are, however, still a matter of debate. Understanding the molecular alterations underlying the disease is crucial for developing new therapeutic strategies. Here, we evaluated the involvement in peritoneal dissemination of the oncogenic isoform of TP73, ΔNp73, and its effector targets in in vitro and mouse models, and in 30 patients diagnosed with colorectal peritoneal metastasis. In an orthotopic mouse model, we observed that tumor cells overexpressing ΔNp73 present a higher avidity for the peritoneum and that extracellular vesicles secreted by ΔNp73-upregulating tumor cells enhance their dissemination. In addition, we identified that tumor cells overexpressing ΔNp73 present with dysregulation of genes associated with an epithelial/mesothelial-to-mesenchymal transition (MMT) and that mesothelial cells exposed to the conditioned medium of tumor cells with upregulated ΔNp73 present a mesenchymal phenotype. Lastly, ΔNp73 and its effector target RNAs were dysregulated in our patient series, there were positive correlations between ΔNp73 and its effector targets, and MSN and ITGB4 (ΔNp73 effectors) predicted patient survival. In conclusion, ΔNp73 and its effector targets are involved in the peritoneal dissemination of colorectal cancer and predict patient survival. The promotion of the EMT/MMT and modulation of the adhesion capacity in colorectal cancer cells might be the mechanisms triggered by ΔNp73. Remarkably, ΔNp73 protein is a druggable protein and should be the focus of future studies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

20 potentially new compounds and 11 new bioactive constituents found in Smilacis Glabrae Rhizoma utilizing HPLC-DAD-ESI-IT-TOF-MSn.

INTRODUCTION: Smilacis Glabrae Rhizoma (SGR) is rich in chemical constituents with a variety of pharmacological activities. However, in-depth research has yet to be conducted on the chemical and pharmacodynamic constituents of SGR. MATERIALS AND METHODS: In this study, the chemical constituents of SGR were analyzed using liquid chromatography-mass spectrometry, and the pharmacodynamic compounds responsible for the medicinal effects of SGR were elucidated through a literature review. RESULTS: In total, 20 potentially new compounds, including 16 flavonoids (C19, C20, and C27-C40) and four phenylpropanoids (C107, C112, C113, and C118), together with 161 known ones were identified in the ethanol extract of SGR using liquid chromatography-mass spectrometry, and 25 of them were unequivocally identified by comparison with reference compounds. Moreover, 17 known constituents of them were identified in the plants of genus Smilax for the first time, and 16 were identified in the plant Smilax glabra Roxb. for the first time. Of 161 known compounds, 84 constituents (including isomers) have been reported to have 17 types of pharmacological activities, covering all known pharmacological activities of SGR; among these 84 bioactive constituents, six were found in the plants of genus Smilax for the first time and five were found in S. glabra for the first time, which are new bioactive constituents found in the plants of genus Smilax and the plant S. glabra, respectively. CONCLUSION: The results provide further information on the chemical composition of SGR, laying the foundation for the elucidation of the pharmacodynamic substances of SGR.

CAPN2-responsive mesoporous silica nanoparticles: A promising nanocarrier for targeted therapy of pancreatic cancer.

Pancreatic adenocarcinoma (PDAC) is highly resistant to conventional chemotherapeutic interventions, resulting in exceptionally low survival rates. The limited efficacy can in part be attributed to dose limitations and treatment cessation urged by toxicity of currently used chemotherapy. The advent of targeted delivery strategies has kindled hope for circumventing off-target toxicity. We have previously reported a PDAC-specific mesoporous silica nanoparticle (MSN) containing a protease linker responsive to ADAM9, a PDAC-enriched extracellularly deposited protease. Upon loading with paclitaxel these ADAM9-MSNs reduced side effects both in vitro and in vivo, however, disappointing antitumor efficacy was observed in vivo. Here, we propose that an efficient uptake of MSNs by tumor cells might underlie the lack of antitumor efficacy of MSNs functionalized with linker responsive to extracellular proteases. Harnessing this premise to improve antitumor efficacy, we performed an in silico analysis to identify PDAC-enriched intracellular proteases. We report the identification of BACE2, CAPN2 and DPP3 as PDAC enriched intracellular proteases, and report the synthesis of BACE2-, CAPN2- and DPP3-responsive MSNs. Extensive preclinical assessments revealed that paclitaxel-loaded CAPN2- and DPP3-MSNs exhibit high PDAC specificity in vitro as opposed to free paclitaxel. The administration of paclitaxel-loaded CAPN2- and DPP3-MSNs in vivo confirmed the reduction of leukopenia and induced no organ damage. Promisingly, in two mouse models CAPN2-MSNs reduced tumor growth at least as efficiently as free paclitaxel. Taken together, our results pose CAPN2-MSNs as a promising nanocarrier for the targeted delivery of chemotherapeutics in PDAC.

Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.

Unveiling the Diversity and Modifications of Short Peptides in Buthus martensii Scorpion Venom through Liquid Chromatography-High Resolution Mass Spectrometry.

More recently, short peptides in scorpion venom have received much attention because of their potential for drug discovery. Although various biological effects of these short peptides have been found, their studies have been hindered by the lack of structural information especially in modifications. In this study, small peptides from scorpion venom were investigated using high-performance liquid chromatography high-resolution mass spectrometry followed by de novo sequencing. A total of 156 sequences consisting of 2~12 amino acids were temporarily identified from Buthus martensii scorpion venom. The identified peptides exhibited various post-translational modifications including N-terminal and C-terminal modifications, in which the N-benzoyl modification was first found in scorpion venom. Moreover, a short peptide Bz-ARF-NH2 demonstrated both N-terminal and C-terminal modifications simultaneously, which is extremely rare in natural peptides. In conclusion, this study provides a comprehensive insight into the diversity, modifications, and potential bioactivities of short peptides in scorpion venom.

Production of 117mSn and 119mSn by photonuclear reactions on natural antimony.

Natural antimony targets were irradiated in a 60 MeV bremsstrahlung beam and gamma spectrometric measurements were performed. The goal was to establish the yield of 117mSn, a radionuclide with great potential for application in medicine. Considering that 117mSn is predominantly produced through a photonuclear reaction in which an charged particle is emitted (121Sb(γ,p3n)), the yield of this tin isotope is much lower than the yields of several antimony isotopes produced in (γ,xn) reactions. It has been estimated that photonuclear reactions on natural antimony could produce 117mSn activities needed for therapeutic applications, with accelerators having electron currents of the order of mA. For the used bremsstrahlung energy of 60 MeV, it was estimated how much 119mSn activity can be expected when exposing the antimony target.

Chromatograms and Mass Spectra of High-Mannose and Paucimannose N-Glycans for Rapid Isomeric Identifications.

N-Linked glycosylation is one of the most essential post-translational modifications of proteins. However, N-glycan structural determination remains challenging because of the small differences in structures between isomers. In this study, we constructed a database containing collision-induced dissociation MSn mass spectra and chromatograms of high-performance liquid chromatography for the rapid identification of high-mannose and paucimannose N-glycan isomers. These N-glycans include isomers by breaking of arbitrary numbers of glycosidic bonds at arbitrary positions of canonical Man9GlcNAc2 N-glycans. In addition, some GlcMannGlcNAc2 N-glycan isomers were included in the database. This database is particularly useful for the identification of the N-glycans not in conventional N-glycan standards. This study demonstrated the application of the database to structural assignment for high-mannose N-glycans extracted from bovine whey proteins, soybean proteins, human mammary epithelial cells, and human breast carcinoma cells. We found many N-glycans that are not expected to be generated by conventional biosynthetic pathways of multicellular eukaryotes.

Deletion of the transcription factors Hsf1, Msn2 and Msn4 in yeast uncovers transcriptional reprogramming in response to proteotoxic stress.

The response to proteotoxic stresses such as heat shock allows organisms to maintain protein homeostasis under changing environmental conditions. We asked what happens if an organism can no longer react to cytosolic proteotoxic stress. To test this, we deleted or depleted, either individually or in combination, the stress-responsive transcription factors Msn2, Msn4, and Hsf1 in Saccharomyces cerevisiae. Our study reveals a combination of survival strategies, which together protect essential proteins. Msn2 and 4 broadly reprogram transcription, triggering the response to oxidative stress, as well as biosynthesis of the protective sugar trehalose and glycolytic enzymes, while Hsf1 mainly induces the synthesis of molecular chaperones and reverses the transcriptional response upon prolonged mild heat stress (adaptation).

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Identification of a transcription factor AoMsn2 of the Hog1 signaling pathway contributes to fungal growth, development and pathogenicity in Arthrobotrys oligospora.

INTRODUCTION: Arthrobotrys oligospora has been utilized as a model strain to study the interaction between fungi and nematodes owing to its ability to capture nematodes by developing specialized traps. A previous study showed that high-osmolarity glycerol (Hog1) signaling regulates the osmoregulation and nematocidal activity of A. oligospora. However, the function of downstream transcription factors of the Hog1 signaling in the nematode-trapping (NT) fungi remains unclear. OBJECTIVE: This study aimed to investigate the functions and potential regulatory network of AoMsn2, a downstream transcription factor of the Hog1 signaling pathway in A. oligospora. METHODS: The function of AoMsn2 was characterized using targeted gene deletion, phenotypic experiments, real-time quantitative PCR, RNA sequencing, untargeted metabolomics, and yeast two-hybrid analysis. RESULTS: Loss of Aomsn2 significantly enlarged and swollen the hyphae, with an increase in septa and a significant decrease in nuclei. In particular, spore yield, spore germination rate, traps, and nematode predation efficiency were remarkably decreased in the mutants. Phenotypic and transcriptomic analyses revealed that AoMsn2 is essential for fatty acid metabolism and autophagic pathways. Additionally, untargeted metabolomic analysis identified an important function of AoMsn2 in the modulation of secondary metabolites. Furtherly, we analyzed the protein interaction network of AoMsn2 based on the Kyoto Encyclopedia of Genes and Genomes pathway map and the online website STRING. Finally, Hog1 and six putative targeted proteins of AoMsn2 were identified by Y2H analysis. CONCLUSION: Our study reveals that AoMsn2 plays crucial roles in the growth, conidiation, trap development, fatty acid metabolism, and secondary metabolism, as well as establishes a broad basis for understanding the regulatory mechanisms of trap morphogenesis and environmental adaptation in NT fungi.

Phenolic Compound Composition of Sambucus nigra L. Wild-Growing Plants from Kosovo.

Objectives: The aim of this study was to determine the phenolic components in the flowers and leaves of wild-growing Sambucus nigra L. Materials and Methods: Plant materials were collected from eleven localities in Kosovo. Before LC-DAD-ESI-MSn analysis, an ultrasonic-assisted method with 70% methanol for 30 min extraction was used. Results: In total, 34 and 37 phenolic compounds were identified in flower and leaf extracts, respectively, with a total content of 61321.82-85961.64 mg/kg dry weight (DW) and 36136.62-93890.37 mg/kg DW. In all of the analyzed extracts, 15 phenolic acids, 20 flavonoids, one lignan, and one coumaroyl iridoid were detected. The major components were flavonoids, especially flavonols (quercetin-3-rutinoside, caffeoyl-kaempferol, and isorhamnetin-3-rutinoside), followed by phenolic acids (dicaffeoylquinic acid isomer, caffeic acid derivative, dicaffeoylquinic acid isomer, and dicaffeoylquinic acid isomer). Conclusion: In general, the methanolic extracts of flowers have shown higher polyphenolic content than those found in leaves. The multivariate statistical analysis of the phenolic content of the samples resulted in PLS-DA models with appropriate correlation coefficients of 0.903 and 0.921 for flower and leaf extracts, respectively. The models revealed distinctive clustering patterns, and the loading scatter plots depicted the unique phenolic compounds specific to each sample group.

Biotransformation of antioxidant eriocitrin into characteristic metabolites by the gut microbiota.

Eriocitrin is a flavonoid glycoside with strong antioxidant capacity that has a variety of pharmacological activities, such as hypolipidemic, anticancer and anti-inflammatory effects. We found that the gut microbiota could rapidly metabolize eriocitrin. By using LC/MSn-IT-TOF, we identified three metabolites of eriocitrin metabolized in the intestinal microbiota: eriodictyol-7-O-glucoside, eriodictyol, and dihydrocaffeic acid. By comparing these two metabolic pathways of eriocitrin (the gut microbiota and liver microsomes), the intestinal microbiota may be the primary metabolic site of eriocitrin metabolism. These findings provide a theoretical foundation for the study of pharmacologically active substances.

Design of a novel nanoparticle to use X-ray fluorescence of TiO2 to induce photodynamic effects in the presence of PpIX.

BACKGROUND: Radiotherapy and photodynamic therapy are the methods of cancer treatment. Although one limitation of photodynamic therapy (PDT) is the limited penetration depth of light through tissue, using X-rays does not have this restriction. Self-lighting nanoparticles can convert X-rays into UV/visible. This study focuses on a newly designed nanostructure containing mesoporous silica nanoparticles (MSN), titanium dioxide nanoparticles (TiO2, anatase grade), and protoporphyrin IX (PpIX) as a photosensitizer to overcome the limitations of photodynamic therapy. METHODS: After the synthesis and characterization of Ti-MSN/PpIX@PVP nanostructure, two ROSes (OH* and 1O2) were measured when the nanostructures were irradiated with 100 kV and 6 MV photons. The toxicity of Ti-MSN/PpIX@PVP nanostructure in presence and absence of radiation was investigated on DFW and HT-29 cell lines. The in-vitro experiments were analyzed using the MTT assay and colony count assay. Finally, the effect of light exposure in the presence of Ti-MSN/PpIX@PVP nanostructure on the two cell lines was studied. The in-vitro studies were evaluated using the Synergism Index (Syn) and Dose Enhancement Factor (DEF). RESULTS: Based on the FESEM (field emission scanning electron Microscopy) images and DLS (dynamic light scattering) measurements, the size of Ti-MSN/PpIX nanostructure was determined as (35.2 nm) and (168.4 nm), respectively. Based on the spectrofluorimetry results, 100 kV photons produced more ROSes than 6 MV photons. The results of MTT assay and colony formation for X-PDT show Syn >1, except for 100 kV photons for HT-29 cell line. The nanostructure also reduced colony formation induced by X-PDT more effectively when irradiated by 100 kV photons on DFW cells. The results obtained from conventional PDT showed that the ED 50 of the HT-29 cell line was 6 times higher than that of the DFW cell line. CONCLUSION: Designing and synthesizing Ti-MSN/PpIX@PVP nanostructures offer a promising strategy for reducing the current challenges in PDT and for developing and advancing X-PDT as an innovative cancer treatment technique.