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Riboflavin-targeted polymers improve tolerance of paclitaxel while maintaining therapeutic efficacy.Nanomedicine : Nanotechnology, Biology,... Jun 2024Active targeting can enhance precision and efficacy of drug delivery systems (DDS) against cancers. Riboflavin (RF) is a promising ligand for active targeting due to its...
Active targeting can enhance precision and efficacy of drug delivery systems (DDS) against cancers. Riboflavin (RF) is a promising ligand for active targeting due to its biocompatibility and high riboflavin-receptor expression in cancers. In this study, RF-targeted 4-arm polyethylene glycol (PEG) stars conjugated with Paclitaxel (PTX), named PEG PTX RF, were evaluated as a targeted DDS. In vitro, PEG PTX RF exhibited higher toxicity against tumor cells compared to the non-targeted counterpart (PEG PTX), while free PTX displayed the highest acute toxicity. In vivo, all treatments were similarly effective, but PEG PTX RF-treated tumors showed fewer proliferating cells, pointing to sustained therapy effects. Moreover, PTX-treated animals' body and liver weights were significantly reduced, whereas both remained stable in PEG PTX and PEG PTX RF-treated animals. Overall, our targeted and non-targeted DDS reduced PTX's adverse effects, with RF targeting promoted drug uptake in cancer cells for sustained therapeutic effect.
Topics: Paclitaxel; Riboflavin; Animals; Humans; Mice; Polyethylene Glycols; Drug Delivery Systems; Cell Line, Tumor; Mice, Inbred BALB C; Polymers; Antineoplastic Agents, Phytogenic; Mice, Nude; Neoplasms; Xenograft Model Antitumor Assays; Female
PubMed: 38705222
DOI: 10.1016/j.nano.2024.102751 -
BMC Public Health May 2024Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to...
BACKGROUND
Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.
METHODS
From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels.
RESULTS
The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration.
CONCLUSIONS
Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.
Topics: Humans; Male; Prostate-Specific Antigen; Middle Aged; Nutrition Surveys; United States; Aged; Prostatic Neoplasms; Riboflavin; Adult
PubMed: 38702746
DOI: 10.1186/s12889-024-18582-y -
Journal of Nanobiotechnology May 2024Bone marrow mesenchymal stem cells (BMSCs) can differentiate into Schwann cells (SCs) during peripheral nerve injury; in our previous research, we showed that SC-derived...
BACKGROUND
Bone marrow mesenchymal stem cells (BMSCs) can differentiate into Schwann cells (SCs) during peripheral nerve injury; in our previous research, we showed that SC-derived exosomes (SC-exos) played a direct induction role while fibroblast-derived exosomes (Fb-exos) had no obvious induction role. The induction role of neural stem cell (NSC)-derived exosomes (NSC-exos) has also been widely confirmed. However, no studies have compared the induction effects of these three types of cells at the same time. Therefore, by investigating the effect of these three cell-derived exosomes upon the induction of BMSCs to differentiate into SCs, this study explored the role of different exosomes in promoting the differentiation of stem cells into SCs cells, and conducted a comparison between the two groups by RNA sequencing to further narrow the range of target genes and related gene pathways in order to study their related mechanisms.
MATERIALS AND METHODS
We extracted exosomes from SCs, fibroblasts (Fb) and neural stem cells (NSC) and then investigated the ability of these exosomes to induce differentiation into BMSCs under different culture conditions. The expression levels of key proteins and gene markers were detected in induced cells by fluorescence immunoassays, western blotting and polymerase chain reaction (PCR); then, we statistically compared the relative induction effects under different conditions. Finally, we analyzed the three types of exosomes by RNA-seq to predict target genes and related gene pathways.
RESULTS
BMSCs were cultured by three media: conventional (no induction), pre-induction or pre-induction + original induction medium (ODM) with exosomes of the same cell origin under different culture conditions. When adding the three different types of exosomes separately, the overall induction of BMSCs to differentiate into SCs was significantly increased (P < 0.05). The induction ability was ranked as follows: pre-induction + ODM + exosome group > pre-induction + exosome group > non-induction + exosome group. Using exosomes from different cell sources under the same culture conditions, we observed the following trends under the three culture conditions: RSC96-exos group ≥ NSC-exos group > Fb-exos group. The overall ability to induce BMSCs into SCs was significantly greater in the RSC96-exos group and the NSC-exos group. Although there was no significant difference in induction efficiency when comparing these two groups, the overall induction ability of the RSC96-exos group was slightly higher than that of the NSC-exos group. By combining the differentiation induction results with the RNA-seq data, the three types of exosomes were divided into three comparative groups: RSC vs. NSC, RSC vs. Fb and NSC vs. Fb. We identified 203 differentially expressed mRNA target genes in these three groups. Two differentially expressed genes were upregulated simultaneously, namely riboflavin kinase (RFK, ENSRNOG00000022273) and ribosomal RNA processing 36 (Rrp36, ENSRNOG00000017836). We did not identify any co-upregulated target genes for the miRNAs, but did identify one target gene of the lncRNAs, namely ENSRNOG00000065005. Analysis identified 90 GO terms related to nerves and axons in the mRNAs; in addition, KEGG enrichment and GASA analysis identified 13 common differential expression pathways in the three groups.
CONCLUSIONS
Our analysis found that pre-induction + ODM + RSC96/NSC-exos culture conditions were most conducive with regards to induction and differentiation. RSC96-exos and NSC-exos exhibited significantly greater differentiation efficiency of BMSCs into SCs. Although there was no statistical difference, the data indicated a trend for RSC96-exos to be advantageous We identified 203 differentially expressed mRNAs between the three groups and two differentially expressed target mRNAs were upregulated, namely riboflavin kinase (RFK, ENSRNOG00000022273) and ribosomal RNA processing 36 (Rrp36, ENSRNOG00000017836). 90 GO terms were related to nerves and axons. Finally, we identified 13 common differentially expressed pathways across our three types of exosomes. It is hoped that the efficiency of BMSCs induction differentiation into SCs can be improved, bringing hope to patients and more options for clinical treatment.
Topics: Exosomes; Schwann Cells; Mesenchymal Stem Cells; Cell Differentiation; Animals; Rats; Cells, Cultured; Fibroblasts; Neural Stem Cells; Rats, Sprague-Dawley; Bone Marrow Cells
PubMed: 38698449
DOI: 10.1186/s12951-024-02450-3 -
Frontiers in Pediatrics 2024Riboflavin transporter deficiency (RTD) is a rare genetic disorder that affects riboflavin transport, leading to impaired red blood cell production and resulting in pure...
INTRODUCTION
Riboflavin transporter deficiency (RTD) is a rare genetic disorder that affects riboflavin transport, leading to impaired red blood cell production and resulting in pure red cell aplasia. Recognizing and understanding its clinical manifestations, diagnosis, and management is important.
CASE PRESENTATION
A 2-year-old patient presented with pure red cell aplasia as the primary symptom of RTD. After confirming the diagnosis, rapid reversal of anemia was achieved after high-dose riboflavin treatment.
CONCLUSION
RTD often has an insidious onset, and neurological symptoms appear gradually as the disease progresses, making it prone to misdiagnosis. Genetic testing and bone marrow biopsy can confirm the diagnosis.
PubMed: 38694724
DOI: 10.3389/fped.2024.1391245 -
The ISME Journal Jan 2024The endosymbiosis between the pathogenic fungus Rhizopus microsporus and the toxin-producing bacterium Mycetohabitans rhizoxinica represents a unique example of host...
The endosymbiosis between the pathogenic fungus Rhizopus microsporus and the toxin-producing bacterium Mycetohabitans rhizoxinica represents a unique example of host control by an endosymbiont. Fungal sporulation strictly depends on the presence of endosymbionts as well as bacterially produced secondary metabolites. However, an influence of primary metabolites on host control remained unexplored. Recently, we discovered that M. rhizoxinica produces FO and 3PG-F420, a derivative of the specialized redox cofactor F420. Whether FO/3PG-F420 plays a role in the symbiosis has yet to be investigated. Here, we report that FO, the precursor of 3PG-F420, is essential to the establishment of a stable symbiosis. Bioinformatic analysis revealed that the genetic inventory to produce cofactor 3PG-F420 is conserved in the genomes of eight endofungal Mycetohabitans strains. By developing a CRISPR/Cas-assisted base editing strategy for M. rhizoxinica, we generated mutant strains deficient in 3PG-F420 (M. rhizoxinica ΔcofC) and in both FO and 3PG-F420 (M. rhizoxinica ΔfbiC). Co-culture experiments demonstrated that the sporulating phenotype of apo-symbiotic R. microsporus is maintained upon reinfection with wild-type M. rhizoxinica or M. rhizoxinica ΔcofC. In contrast, R. microsporus is unable to sporulate when co-cultivated with M. rhizoxinica ΔfbiC, even though the fungus was observed by super-resolution fluorescence microscopy to be successfully colonized. Genetic and chemical complementation of the FO deficiency of M. rhizoxinica ΔfbiC led to restoration of fungal sporulation, signifying that FO is indispensable for establishing a functional symbiosis. Even though FO is known for its light-harvesting properties, our data illustrate an important role of FO in inter-kingdom communication.
Topics: Symbiosis; Rhizopus; Spores, Fungal; Flavins; CRISPR-Cas Systems; Riboflavin
PubMed: 38691425
DOI: 10.1093/ismejo/wrae074 -
Synthetic and Systems Biotechnology Sep 2024Vitamin B is an essential water-soluble vitamin. For most prokaryotes, a bifunctional enzyme called FAD synthase catalyzes the successive conversion of riboflavin to FMN...
Vitamin B is an essential water-soluble vitamin. For most prokaryotes, a bifunctional enzyme called FAD synthase catalyzes the successive conversion of riboflavin to FMN and FAD. In this study, the plasmid pNEW-AZ containing six key genes for the riboflavin synthesis was transformed into strain R2 with the deleted FMN riboswitch, yielding strain R5. The R5 strain could produce 540.23 ± 5.40 mg/L riboflavin, which was 10.61 % higher than the R4 strain containing plasmids pET-AE and pAC-Z harboring six key genes. To further enhance the production of riboflavin, homology matching and molecular docking were performed to identify key amino acid residues of FAD synthase. Nine point mutation sites were identified. By comparing riboflavin kinase activity, mutations of T203D and N210D, which respectively decreased by 29.90 % and 89.32 % compared to wild-type FAD synthase, were selected for CRISPR/Cas9 gene editing of the genome, generating engineered strains R203 and R210. pNEW-AZ was transformed into R203, generating R6. R6 produced 657.38 ± 47.48 mg/L riboflavin, a 21.69 % increase compared to R5. This study contributes to the high production of riboflavin in recombinant BL21.
PubMed: 38680946
DOI: 10.1016/j.synbio.2024.04.011 -
Nature Communications Apr 2024Modified cyclic dipeptides represent a widespread class of secondary metabolites with diverse pharmacological activities, including antibacterial, antifungal, and...
Modified cyclic dipeptides represent a widespread class of secondary metabolites with diverse pharmacological activities, including antibacterial, antifungal, and antitumor. Here, we report the structural characterization of the Streptomyces noursei enzyme AlbAB, a cyclodipeptide oxidase (CDO) carrying out α,β-dehydrogenations during the biosynthesis of the antibiotic albonoursin. We show that AlbAB is a megadalton heterooligomeric enzyme filament containing covalently bound flavin mononucleotide cofactors. We highlight that AlbAB filaments consist of alternating dimers of AlbA and AlbB and that enzyme activity is crucially dependent on filament formation. We show that AlbA-AlbB interactions are highly conserved suggesting that other CDO-like enzymes are likely enzyme filaments. As CDOs have been employed in the structural diversification of cyclic dipeptides, our results will be useful for future applications of CDOs in biocatalysis and chemoenzymatic synthesis.
Topics: Streptomyces; Bacterial Proteins; Dipeptides; Oxidoreductases; Flavin Mononucleotide; Peptides, Cyclic; Crystallography, X-Ray; Models, Molecular; Anti-Bacterial Agents
PubMed: 38678027
DOI: 10.1038/s41467-024-48030-9 -
Life (Basel, Switzerland) Apr 2024This study aimed to evaluate the association between the dietary intake of vitamin B complex (thiamine, riboflavin, and niacin) and cervical cancer in Korea.
BACKGROUND
This study aimed to evaluate the association between the dietary intake of vitamin B complex (thiamine, riboflavin, and niacin) and cervical cancer in Korea.
METHODS
The data from the Korean National Health and Nutrition Examination Survey (KNHANES) from 2010 to 2021 were analyzed, which included 28,306 participants who were categorized into non-cervical cancer and cervical cancer groups. The following dietary intake threshold levels of thiamine, riboflavin, and niacin were identified based on the recommended daily allowances (RDAs): thiamine, 1.1 mg/day; riboflavin, 1.2 mg/day; and niacin, 14 mg/day.
RESULTS
Among 28,306 participants, 27,976 were in the non-cervical cancer group and 330 were in the cervical cancer group. Riboflavin intakes of more than 1.2 mg/day but less than 2.4 mg/day were associated with a significantly reduced risk of cervical cancer, whereas intakes of above 2.4 mg/day were not associated with cervical cancer. Thiamine and niacin intakes were not significantly related to the risk of cervical cancer.
CONCLUSIONS
The results of this study suggest that an intake of riboflavin of 1.2-2.4 mg/day may contribute to a lower risk of cervical cancer.
PubMed: 38672799
DOI: 10.3390/life14040529 -
Biology Apr 2024The application of synthetic biology tools to modulate gene expression to increase yield has been thoroughly demonstrated as an effective and convenient approach in...
The application of synthetic biology tools to modulate gene expression to increase yield has been thoroughly demonstrated as an effective and convenient approach in industrial production. In this study, we employed a high-throughput screening strategy to identify a 5' UTR sequence from the genome of 168. This sequence resulted in a 5.8-fold increase in the expression level of EGFP. By utilizing the 5' UTR sequence to overexpress individual genes within the operon, it was determined that the genes and serve as rate-limiting enzymes in the riboflavin synthesis pathway. Constructing a 5' UTR library to regulate EGFP expression resulted in a variation range in gene expression levels exceeding 100-fold. Employing the same 5' UTR library to regulate the expression of EGFP and mCherry within the operon led to a change in the expression ratio of these two genes by over 10,000-fold. So, employing a 5' UTR library to modulate the expression of the operon gene and construct a synthetic operon resulted in a 2.09-fold increase in riboflavin production. These results indicate that the 5' UTR sequence identified and characterized in this study can serve as a versatile synthetic biology toolkit for achieving complex metabolic network reconstruction. This toolkit can facilitate the fine-tuning of gene expression to produce target products.
PubMed: 38666889
DOI: 10.3390/biology13040277 -
Heliyon Apr 2024Intestinal bacteria significantly contribute to the metabolism of intestinal epithelial tissues. As the occurrence and development of radiation enteritis (RE) depend on...
BACKGROUND
Intestinal bacteria significantly contribute to the metabolism of intestinal epithelial tissues. As the occurrence and development of radiation enteritis (RE) depend on the "co-metabolism" microenvironment formed by the host and intestinal microbiota, which involves complex influencing factors and strong correlations, ordinary techniques struggle to fully explain the underlying mechanisms. However, given that it is based on systems biology, metabolomics analysis is well-suited to address these issues. This study aimed to analyze the metabolomic changes in urine, serum, and fecal samples during volumetric modulated arc therapy (VMAT) for cervical cancer and screen for characteristic metabolites of severe acute radiation enteritis (SARE) and RE.
METHODS
We enrolled 50 patients who received radiotherapy for cervical cancer. Urine, serum, and fecal samples of patients were collected at one day before radiotherapy and the second week, fourth week, and sixth week after the start of radiotherapy. Control group samples were collected during the baseline period. Differential metabolites were identified by metabolomics analysis; co-metabolic pathways were clarified. We used the mini-SOM library for incorporating characteristic metabolites, and established metabolite classification models for predicting SARE and RE.
RESULTS
Urine and serum sample data showed remarkable clustering effect; metabolomics data of the fecal supernatant were evidently disturbed. Patient sample analyses during VMAT revealed the following. : Downregulation of the pyrimidine and riboflavin metabolism pathways as well as initial upregulation followed by downregulation of arginine and proline metabolism pathways and the arginine biosynthesis pathway. : Upregulation of linoleic acid and phenylalanine metabolic pathways and initial downregulation followed by upregulation of arachidonic acid (AA) metabolic pathways. : Initial upregulation followed by downregulation of the arginine biosynthesis pathway and downregulation of glutathione, AA, and arginine and proline metabolic pathways.
CONCLUSION
Patients with cervical cancer exhibited characteristic metabolic pathways and characteristic metabolites predicting RE and SARE were screened out. An effective RE mini-SOM classification model was successfully established.
PubMed: 38655340
DOI: 10.1016/j.heliyon.2024.e29598