Anti-virulence potential of iclaprim, a novel folic acid synthesis inhibitor, against Staphylococcus aureus.

Infections caused by Staphylococcus aureus pose a significant global public problem. Therefore, new antibiotics and therapeutic strategies are needed to combat this pathogen. This investigation delves into the effects of iclaprim, a newly discovered inhibitor of folic acid synthesis, on S. aureus virulence. The phenotypic and genotypic effects of iclaprim were thoroughly examined in relation to virulence factors, biofilm formation, and dispersal, as well as partial virulence-encoding genes associated with exoproteins, adherence, and regulation in S. aureus MW2, N315, and ATCC 25923. Then, the in vivo effectiveness of iclaprim on S. aureus pathogenicity was explored by a Galleria mellonella larvae infection model. The use of iclaprim at sub-inhibitory concentrations (sub-MICs) resulted in a reduction of α-hemolysin (Hla) production and a differential effect on the activity of coagulase in S. aureus strains. The results of biofilm formation and eradication assay showed that iclaprim was highly effective in depolymerizing the mature biofilm of S. aureus strains at concentrations of 1 MIC or greater, however, inhibited the biofilm-forming ability of only strains N315 and ATCC 25923 at sub-MICs. Interestingly, treatment of strains with sub-MICs of iclaprim resulted in significant stimulation or suppression of most virulence-encoding genes expression. Iclaprim did not affect the production of δ-hemolysin or staphylococcal protein A (SpA), nor did it impact the total activity of proteases, nucleases, and lipases. In vivo testing showed that sub-MICs of iclaprim significantly improves infected larvae survival. The present study offered valuable insights towards a better understating of the influence of iclaprim on different strains of S. aureus. The findings suggest that iclaprim may have potential as an anti-virulence and antibiofilm agent, thus potentially mitigating the pathogenicity of S. aureus and improving clinical outcomes associated with infections caused by this pathogen. KEY POINTS: • Iclaprim effectively inhibits α-hemolysin production and biofilm formation in a strain-dependent manner and was an excellent depolymerizing agent of mature biofilm • Iclaprim affected the mRNA expression of virulence-encoding genes associated with exoproteins, adherence, and regulation • In vivo study in G. mellonella larvae challenged with S. aureus exhibited that iclaprim improves larvae survival.

Targeted biocompatible Zn-metal-organic framework nanocomposites for intelligent chemotherapy of breast cancer cells.

Finding a novel drug delivery system (DDS) represents one of the most challenging endeavors in cancer therapy. Hence, in this study, we developed a new biocompatible and biodegradable zinc-based nanoscale metal-organic framework (Zn-NMOF) coated with folic acid (FA) functionalized chitosan (CS) to facilitate targeted delivery of doxorubicin (D), a standard chemotherapeutic agent, into breast cancer cells. The synthesis of the NMOF-CS-FA-D nanocomposite preceded its comprehensive characterization via FT-IR, DLS, XRD, SEM, and TEM analyses. Subsequent in vitro studies were conducted on MCF-7 breast cancer cells and HFF-1 normal cells, encompassing assessments of cell viability, expression levels of apoptotic and autophagy genes, cell cycle arrest, and apoptotic analyses. The size of the NMOF-CS-FA-D particles was determined to be less than 80 nm, with a drug loading efficiency of 72 ± 5%. The release kinetics of DOX from the nanocomposite were investigated, revealing controlled release behavior at pH 7.4 and accelerated release at pH 5.0, which is conducive to drug delivery into cancer cells. In vitro results indicated a 17.39% ± 6.34 cell viability after 24 h of treatment with a 40 nM concentration of the NMOF-CS-FA-D nanocomposite. Furthermore, the expression levels of Caspase-9 and BAX, key apoptotic genes, along with BECLIN1, an autophagy gene, were found to increase by two-fold, four-fold, and two-fold, respectively, following 5 h of treatment with the nanocomposite. Additionally, analysis of cell cycle distribution revealed 15.4 ± 2% of cells in the sub-G1 phase, indicative of apoptotic cells, and 31.9% of cells undergoing early and late apoptosis in MCF-7 cells. Collectively, these findings underscore the potential of the NMOF-CS-FA-D nanocomposite in inhibiting cancer cell proliferation with low side effects.

Ocoxin Oral Solution Triggers DNA Damage and Cell Death in Ovarian Cancer.

Ovarian cancer is the most fatal of all the reproductive cancers within the female population, mainly due to its late diagnosis that limits surgery and medical treatment. Classically, ovarian cancer therapy has included conventional chemotherapy, and other therapeutic approaches are now being used to treat these patients, but the outcomes of the disease are still poor. Therefore, new strategies are needed to improve life expectancy and life quality of ovarian cancer patients. Considering that, we investigated the effect of the nutritional supplement Ocoxin Oral Solution (OOS) in ovarian cancer models. OOS contains several nutritional supplements, some of them with demonstrated antitumoral action. In vitro studies showed that OOS inhibited the proliferation of several ovarian cancer cell lines, especially of those representative of the endometrioid subtype, in a time- and dose-dependent manner. A fast cell death induction after OOS treatment was observed, and when the molecular mechanisms leading to this effect were investigated, an activation of the DNA damage checkpoint was detected, as shown by activation (phosphorylation) of CHK1 and CHK2 kinases that was followed by the phosphorylation of the target protein histone H2AX. When tested in animal models of ovarian cancer, OOS reduced tumor growth without any observed secondary effects. Moreover, such reduction in tumor proliferation was caused by the induction of DNA damage as corroborated by the in vivo phosphorylation of CHK2 and Histone H2AX. Finally, OOS potentiated the action of carboplatin or olaparib, the standard of care treatments used in ovarian clinics, opening the possibility of including OOS in combination with those standard of care agents in patients with ovarian cancer.

Dual-Targeted Zeolitic Imidazolate Frameworks Drug Delivery System Reversing Cisplatin Resistance to Treat Resistant Ovarian Cancer.

Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.

Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration.

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways.

Development of folate-conjugated polypyrrole nanoparticles incorporated with nitrogen-doped carbon quantum dots for targeted bioimaging and photothermal therapy.

PPy nanoparticles are widely employed as PTT agents, because of their exceptional near-infrared absorption properties. Nonetheless, the efficacy of PTT with PPy nanoparticles is hindered by a challenge, specifically, a lack of precise targeting. In this study, a PTT imaging agent was developed by combining NCQDs having bright green fluorescent properties with PPy nanoparticles along with the masking of folic acid to overcome the challenge of targeting. The synthesized PPy:NCQDs:FA nanocomposite, characterized by extraordinary photothermal property, was utilized for imaging of folate receptor positive (FA+) MCF-7 cancer cells through the emission of green fluorescence by NCQDs incorporated within the nanocomposite. Additionally, these nanoparticles demonstrated a good level of cell viability, exceeding 82 %, even at a concentration of 600 µg mL-1. Even the in vivo toxicity inspection of the nanocomposite exemplified no observed acute toxicity at experimental dosages of 1 and 3 mg per kg body weight. By subjecting MCF-7 cells, inoculated with 100 µg mL-1 of nanocomposite, to NIR laser irradiation for 5 min, a significant decline in cell viability was witnessed, establishing the photothermal therapeutic potency of the nanocomposite. The death of cancer cells induced by nanocomposite was verified through MTT assay, imaging of cells by NCQDs alone, with nanocomposite, and by live/dead cell Calcein AM/PI staining assay. Quantification of induced apoptosis post-laser treatment is conducted through staining with Annexin V-FITC/PI. These findings establish potential use of PPy:NCQDs:FA nanocomposite as versatile theranostic agents, capable of targeted bioimaging and treatment for cancer cells exhibiting folate receptors.

Multibiofunctional Self-healing Adhesive Injectable Nanocomposite Polysaccharide Hydrogel.

Injectable hydrogels with good antimicrobial and antioxidant properties, self-healing characteristics, suitable mechanical properties, and therapeutic effects have great practical significance for developing treatments for pressing healthcare challenges. Herein, we have designed a novel, self-healing injectable hydrogel composite incorporating cross-linked biofunctional nanomaterials by mixing alginate aldehyde (Ox-Alg), quaternized chitosan (QCS), adipic acid dihydrazide (ADH), and copper oxide nanosheets surface functionalized with folic acid as the bioligand (F-CuO). Gelation was achieved under physiological conditions via the dynamic Schiff base cross-linking mechanism. The developed nanocomposite injectable hydrogel demonstrated the fast self-healing ability essential to bear deformation and outstanding antibacterial properties along with ROS scavenging ability. Furthermore, the optimized formulation of our F-CuO-embedded injectable hydrogel exhibited excellent cytocompatibility, blood compatibility, and in vitro wound healing performance. Taken together, the F-CuO nanosheet cross-linked injectable hydrogel composite presented herein offers a promising candidate biomaterial with multifunctional properties to develop solutions for addressing clinical challenges.

Novel Role of 5-Methyl-(6S)-Tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension.

BACKGROUND: Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effects of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5-MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remain unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy and the possible consequences for endothelial NO generation, maternal blood pressure, and fetal growth. METHODS: We analyzed the maternal blood pressure in pregnant wild-type (Gch1fl/fl) and Gch1fl/fl Tie2cre mice treated with either FA or 5-MTHF starting before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by high-performance liquid chromatography. RESULTS: In vitro studies in mouse and human endothelial cells showed that treatment with 5-MTHF, but not FA, elevated BH4 levels, reduced superoxide production, and increased NO synthase activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NO synthase activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented and treated hypertension in pregnancy when administered either before or during pregnancy, respectively, and normalized placental and fetal growth restriction if administered from mid-gestation onward. CONCLUSIONS: Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NO synthase activity. Thus, 5-MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.

Folic acid-modified nanocrystalline cellulose for enhanced delivery and anti-cancer effects of crocin.

Crocin is a carotenoid compound in saffron with anti-cancer properties. However, its therapeutic application is limited by its low absorption, bioavailability, and stability, which can be overcome through nanocarrier delivery systems. This study used surface-modified Nano-crystalline cellulose (NCC) to deliver crocin to cancer cells. NCC modified with CTAB were loaded with crocin and then conjugated with folic acid (NCF-CR-NPs). The synthesized nanoparticles (NPs) were characterized using FTIR, XRD, DLS, and FESEM. The crystallinity index of NCC was 66.64%, higher than microcrystalline cellulose (61.4%). The crocin loading and encapsulation efficiency in NCF-CR-NPs were evaluated. Toxicity testing by MTT assay showed that NCF-CR-NPs had higher toxicity against various cancer cell lines, including colon cancer HT-29 cells (IC50 ~ 11.6 µg/ml), compared to free crocin. Fluorescent staining, flow cytometry, and molecular analysis confirmed that NCF-CR-NPs induced apoptosis in HT-29 cells by increasing p53 and caspase 8 expression. The antioxidant capacity of NCF-CR-NPs was also evaluated using ABTS and DPPH radical scavenging assays. NCF-CR-NPs exhibited high free radical scavenging ability, with an IC50 of ~ 46.5 µg/ml for ABTS. In conclusion, this study demonstrates the potential of NCF-CR-NPs to deliver crocin to cancer cells effectively. The NPs exhibited enhanced anti-cancer and antioxidant activities compared to free crocin, making them a promising nanocarrier system for crocin-based cancer therapy.

The therapeutic effect and MR molecular imaging of FA-PEG-FePt/DDP nanoliposomes in AMF on ovarian cancer.

Purpose: This study aimed to construct targeting drug-loading nanocomposites (FA-FePt/DDP nanoliposomes) to explore their potential in ovarian cancer therapy and molecular magnetic resonance imaging (MMRI). Methods: FA-FePt-NPs were prepared by coupling folate (FA) with polyethylene-glycol (PEG)-coated ferroplatinum nanoparticles and characterized. Then cisplatin (DDP) was encapsulated in FA-FePt-NPs to synthesize FA-PEG-FePt/DDP nanoliposomes by thin film-ultrasonic method and high-speed stirring, of which MMRI potential, magnetothermal effect, and the other involved performance were analyzed. The therapeutic effect of FA-FePt/DDP nanoliposomes combined with magnetic fluid hyperthermia (MFH) on ovarian cancer in vitro and in vivo was evaluated. The expression levels of Bax and epithelial-mesenchymal transition related proteins were detected. The biosafety was also preliminarily observed. Results: The average diameter of FA-FePt-NPs was about 30 nm, FA-FePt/DDP nanoliposomes were about 70 nm in hydrated particle size, with drug slow-release and good cell-specific targeted uptake. In an alternating magnetic field (AMF), FA-FePt/DDP nanoliposomes could rapidly reach the ideal tumor hyperthermia temperature (42~44 °C). MRI scan showed that FA-FePt-NPs and FA-FePt/DDP nanoliposomes both could suppress the T2 signal, indicating a good potential for MMRI. The in vitro and in vivo experiments showed that FA-FePt/DDP-NPs in AMF could effectively inhibit the growth of ovarian cancer by inhibiting cancer cell proliferation, invasion, and migration, and inducing cancer cell apoptosis, much better than that of the other individual therapies; molecularly, E-cadherin and Bax proteins in ovarian cancer cells and tissues were significantly increased, while N-cadherin, Vimentin, and Bcl-2 proteins were inhibited, effectively inhibiting the malignant progression of ovarian cancer. In addition, no significant pathological injury and dysfunction was observed in major visceras. Conclusion: We successfully synthesized FA-FePt/DDP nanoliposomes and confirmed their good thermochemotherapeutic effect in AMF and MMRI potential on ovarian cancer, with no obvious side effects, providing a favorable strategy of integrated targeting therapy and diagnosis for ovarian cancer.

Curcumin loaded ß-cyclodextrin-magnetic graphene oxide nanoparticles decorated with folic acid receptors as a new theranostic agent to improve prostate cancer treatment.

This article presents a novel approach to treating prostate cancer using a nanocarrier composed of folic acid (FA), ß-cyclodextrin (ß-CD), and magnetic graphene oxide (MGO) as a theranostic agent. The carrier is designed to improve the solubility and bioavailability of curcumin, a potential therapeutic substance against prostate cancer. Folic acid receptors overexpressed on the surface of solid tumors, including prostate cancer, may facilitate targeted drug delivery to tumor cells while avoiding nonspecific effects on healthy tissues. The anticancer efficacy of Folic acid-curcumin@ß-CD-MGO in vitro was also examined on LNCaP (an androgen-dependent) and PC3 (an androgen-independent) prostate cancer cells. The relaxivity of nanoparticles in MRI images was also investigated as a diagnostic factor. The results showed a concentration-dependent inhibitory effect on cell proliferation, induction of oxidative damage, and apoptotic effects. Also, nanoparticle relaxometry shows that this agent can be used as a negative contrast agent in MRI images. Overall, this study represents a promising theranostic agent to improve the delivery and trace of curcumin and enhance its therapeutic potential in the treatment of prostate cancer.

Synergistic Coassembly of Folic Acid-Based Supramolecular Polymer with a Covalent Polymer Toward Fabricating Functional Antibacterial Biomaterials.

Supramolecular biomaterials can recapitulate the structural and functional facets of the native extracellular matrix and react to biochemical cues, leveraging the unique attributes of noncovalent interactions, including reversibility and tunability. However, the low mechanical properties of supramolecular biomaterials can restrict their utilization in specific applications. Combining the advantages of supramolecular polymers with covalent polymers can lead to the fabrication of tailor-made biomaterials with enhanced mechanical properties/degradability. Herein, we demonstrate a synergistic coassembled self-healing gel as a multifunctional supramolecular material. As the supramolecular polymer component, we chose folic acid (vitamin B9), an important biomolecule that forms a gel comprising one-dimensional (1D) supramolecular polymers. Integrating polyvinyl alcohol (PVA) into this supramolecular gel alters its ultrastructure and augments its mechanical properties. A drastic improvement of complex modulus (G*) (∼3674 times) was observed in the folic acid-PVA gel with 15% w/v PVA (33215 Pa) compared with the folic acid gel (9.04 Pa). The coassembled hydrogels possessed self-healing and injectable/thixotropic attributes and could be printed into specific three-dimensional (3D) shapes. Synergistically, the supramolecular polymers of folic acid also improve the toughness, durability, and ductility of the PVA films. A nanocomposite of the gels with silver nanoparticles exhibited excellent catalytic efficiency and antibacterial activity. The folic acid-PVA coassembled gels and films also possessed high cytocompatibility, substantiated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and live-dead assays. Taken together, the antibacterial and cell-adhesive attributes suggest potential applications of these coassembled biomaterials for tissue engineering and wound healing.

Preparation of novel sulfated polysaccharide-carboxymethyl-5-fluorouracil-folic acid conjugates for targeted anticancer drug delivery.

GFP1, a sulfated polysaccharide extracted from Grateloupia filicina, exhibits remarkable immunomodulatory activity. To reduce the side effects of 5-fluorouracil (5-FU), GFP1 was employed as a macromolecular carrier to synthesize of GFP1-C-5-FU by reacting with carboxymethyl-5-fluorouracil (C-5-FU). Subsequently, this new compound was reacted with folic acid (FA) through an ester bond, forming novel conjugates named GFP1-C-5-FU-FA. Nuclear magnetic resonance analysis confirmed the formation of GFP1-C-5-FU-FA. In vitro drug release studies revealed that the cumulative release rate of C-5-FU reached 46.9 % in phosphate buffer (pH 7.4) after 96 h, a rate significantly higher than that of the control groups, indicating the controlled drug release behavior of GFP1-C-5-FU-FA. Additionally, in vitro anticancer assays demonstrated the potent anticancer activity of GFP1-C-5-FU-FA conjugates, as evidenced by the reduced viability of HeLa and AGS cancer cells, along with increased levels of apoptosis and cellular uptake. Western blot analysis indicated that the GFP1-C-5-FU-FA conjugate effectively enhanced phosphorylation in cancer cells through the NF-kB and MAPK pathways, thereby promoting apoptosis. These findings highlight the potential of folate-targeted conjugates in efficiently treating HeLa and AGS cancer cells in vitro and lay a robust theoretical groundwork for future in vivo anti-cancer research involving these cells.

Galectin-8 counteracts folic acid-induced acute kidney injury and prevents its transition to fibrosis.

Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pre-treatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression.

Folic acid and S-adenosylmethionine reverse Homocysteine-induced Alzheimer's disease-like pathological changes in rat hippocampus by modulating PS1 and PP2A methylation levels.

BACKGROUND: Abnormally elevated homocysteine (Hcy) is recognized as a biomarker and risk factor for Alzheimer's disease (AD). However, the underlying mechanisms by which Hcy affects AD are still unclear. OBJECTIVES: This study aimed to elucidate the effects and mechanisms by which Hcy affects AD-like pathological changes in the hippocampus through in vivo and in vitro experiments, and to investigate whether folic acid (FA) and S-adenosylmethionine (SAM) supplementation could improve neurodegenerative injuries. METHODS: In vitro experiments hippocampal neurons of rat were treated with Hcy, FA or SAM for 24 h; while the hyperhomocysteinemia (HHcy) in Wistar rats was established by intraperitoneal injection of Hcy, and FA was added to feed. The expression of ß-amyloid (Aß), phosphorylated tau protein, presenilin 1 (PS1) at the protein level and the activity of protein phosphatase 2A (PP2A) were detected, the immunopositive cells for Aß and phosphorylated tau protein in the rat hippocampus were also evaluated by immunohistochemical staining. RESULTS: FA and SAM significantly repressed Hcy-induced AD-like pathological changes in the hippocampus, including the increased tau protein phosphorylation at Ser214, Ser396 and the expression of Aß42. In addition, Hcy-induced PS1 expression increased at the protein level and PP2A activity decreased, while FA and SAM were able to retard that. CONCLUSIONS: The increase in PS1 expression and decrease in PP2A activity may be the mechanisms underlying the Hcy-induced AD-like pathology. FA and SAM significantly repressed the Hcy-induced neurodegenerative injury by modulating PS1 and PP2A methylation levels.

Chitosan-grafted folic acid decorated one-dimensional GONS: A biocompatible drug cargo for targeted co-delivery of anticancer agents.

In conventional chemotherapy, the cancer cells can become highly resilient due to a phenomenon known as multi-drug resistance (MDR). The co-delivery of chemotherapeutic agents assisted with novel nanocarrier-based targeted DDS may counter the MDR issues and subsequently improve their therapeutic efficacy. In line with this, the present work deals with the development of 1D graphene oxide nanoscrolls (GONS)-based nano delivery system for co-delivery of chemosensitizer along with the chemotherapeutic agent. Herein, the 1D GONS nanocarrier was initially functionalized with chitosan (CS) biopolymer and folic acid (FA) further to enhance their biocompatibility and target-specific co-delivery. The resultant GONS-CS-FA (GCF) nanocarriers were co-loaded with doxorubicin (DOX) and caffeic acid (CA) at different weight proportions with respect to nanocarrier and drug composition. The optimum loading efficiency of 51.14 ± 1.47 % (DOX) and 49.70 ± 1.19 % (CA) was observed for GCF: drug ratio of 2.5 with drug composition of 1:1. In vitro release at pH 5 yielded ~83 % DOX and 75 % CA, compared to ~71 % DOX and 61 % CA at pH 7.4 over 7 days, suggesting a higher and targeted drug release in the cancer microenvironment. Cytotoxicity tests revealed selective apoptosis in cancer cells (A549) while maintaining cytocompatibility with normal cells (HEK293).

Targeting SRD5A1 and MMP-2/NLRP3/TGF-ß1 axis alleviates the amlodipine-induced gingival hyperplasia in rats: Emerging role of saw palmetto and folic acid.

Saw palmetto (SAW), the herbal drug used to treat prostatic hyperplasia, exerts its antiproliferative effects by blocking steroid 5 alpha-reductase (SRD5A1) activity, that has also been involved in gingival hyperplasia (GH) pathogenesis. Concurrently, folic acid (FA) could reduce GH prevalence via its antioxidant and anti-inflammatory effects. Thus, this study tended to assess the potential therapeutic efficacy of SAW, alone and along with FA, against amlodipine-induced gingival inflammation and overgrowth in rats. Rats were grouped into (CONT, AIGH, SAW, SAW-treated, FA-treated, and SAW + FA-treated). SAW and FA were administered once daily for 4 weeks. Gingival SRD5A1, CTGF, GSK-3ß, and NLRP3 expressions, as well as T, DHT, MDA, TAC, ET-1, and MMP2 levels were determined. In addition, histopathological and immunohistochemical analyses of TNF-α, IL-6, TGF-ß1, and α-SMA were documented. Results declared that SAW and FA administration markedly ameliorated amlodipine-associated GH and may be presenting a novel therapeutic avenue in the future.

Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis.

BACKGROUND: In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. PURPOSE: In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. METHODS: We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. RESULTS: Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. CONCLUSION: This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.

In vitro studies of hemoglobin's affinity for the Vitamin B9 and control of its stability character.

Vitamin B9, known as folic acid, and hemoglobin play an important biological role in the human body. This study was designed to investigate the nature of the complex through multispectroscopic methods at physiological conditions due to the lack of research on the binding interactions between folic acid and hemoglobin. Structural analysis showed that the interactions between the molecules are mainly hydrophobic with binding constant of 0.73 × 104 L/mol at 37 °C. The secondary structure of the protein was stable after the addition of folic acid with a 20-fold excess of ligand per mol protein. The stability effect of folic acid on hemoglobin was examined as a function of release of iron ions and determination of the level of phenanthroline-Fe2+ complex. The protective function of folic acid was observed at a concentration of 6.12 nmol/L, and the release of iron ions was lower than in the control probe.

Impact of varying maternal dietary folate intake on cerebellar cortex histomorphology and cell density in offspring rats.

The cerebellum has a long, protracted developmental period that spans from the embryonic to postnatal periods; as a result, it is more sensitive to intrauterine and postnatal insults like nutritional deficiencies. Folate is crucial for foetal and early postnatal brain development; however, its effects on cerebellar growth and development are unknown. The aim of this study was to examine the effects of maternal folate intake on the histomorphology and cell density of the developing cerebellum. Twelve adult female rats (rattus norvegicus) were randomly assigned to one of four premixed diet groups: standard (2 mg/kg), folate-deficient (0 mg/kg), folate-supplemented (8 mg/kg) or folate supra-supplemented (40 mg/kg). The rats started their diets 14 days before mating and consumed them throughout pregnancy and lactation. On postnatal days 1, 7, 21 and 35, five pups from each group were sacrificed, and their brains were processed for light microscopic analysis. Histomorphology and cell density of the external granule, molecular, Purkinje and internal granule layers were obtained. The folate-deficient diet group had smaller, dysmorphic cells and significantly lower densities of external granule, molecular, Purkinje and internal granule cells. Although the folate-enriched groups had greater cell densities than the controls, the folate-supplemented group had considerably higher cell densities than the supra-supplemented group. The folate supra-supplemented group had ectopic Purkinje cells in the internal granule cell layer. These findings imply that a folate-deficient diet impairs cellular growth and reduces cell density in the cerebellar cortex. On the other hand, folate supplementation increases cell densities, but there appears to be an optimal dose of supplementation since excessive folate levels may be detrimental.