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Update of Res Sq. 2024 Jan 12:rs.3.rs-3787917. doi: 10.21203/rs.3.rs-3787917/v1. Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effe

BACKGROUND: To evaluate the safety and efficacy of a newly developed catheter coated with antimicrobial poly-L-lysine (PLL) in reducing the risk of catheter-associated bacteriuria. METHODS: A prospective, multicenter, randomized controlled noninferiority trial was conducted among patients who required indwelling catheterization between February 23, 2023, and January 30, 2024. The experimental group used antimicrobial PLL catheters, and the control group used noble metal alloys (NMA) coated catheters. The primary outcome was the incidence of catheter-associated bacteriuria. The secondary outcome was the total bacterial count per unit surface area of the catheter body in the urethra after catheterization. The safety evaluation included complications related to catheterization. The noninferiority threshold was set at 10%. RESULTS: Three hundred patients were enrolled, while the full analysis set (FAS) included 150 patients who received PLL catheters and 150 patients who received NMA catheters. There were 10 cases (6.9%) of bacteriuria in the experimental group and 15 cases (10.1%) in the control group. The difference in the incidence of bacteriuria between the experimental and control groups was - 3.1% (95% CI [- 7.2%, 6.6%], p = 0.3195). Four patients experienced symptoms compared to 6 in the control group during catheterization (p = 0.750). The proportion of patients experiencing abnormal urine white blood cells in the experimental group was lower (6.2% vs. 12.8%, p = 0.0194). The incidence of catheter-related adverse events was 3 cases (2.0%) in the experimental group and 6 cases (4.0%) in the control group (p = 0.5011). CONCLUSIONS: The short-term use of PLL catheters demonstrated noninferior efficacy in preventing bacteriuria compared with NMA catheters. The PLL catheters have good safety profile and low toxicity. Further trials involving more patients and long duration period are imperative to demonstrate the generalizability of the findings. TRIAL REGISTRATION: This study was registered at https://www.chictr.org.cn/showproj.html?proj=188879 on February 3, 2023, and ID is ChiCTR2200059331. © 2026. The Author(s).

BACKGROUND AND AIM: Provision of dietary counselling has been shown to improve dietary quality, cardiometabolic risk factors (CMRF) and mental health, but these beneficial effects are not well studied in Asian older women. Thus, this study aimed to assess the impact of dietary counselling on CMRF, mental health parameters and dietary quality in Singapore older women. METHODS AND RESULTS: This was a 12-week, parallel design, randomized controlled trial and 39 older women (mean age of 67.5 years old) recruited from a senior activity center in Singapore were randomized to the control group (n = 19) or the intervention group (n = 20). Only subjects in the intervention group received high intensity dietary counselling for 12 weeks while the control group maintained their lifestyle. Dietary quality based on the alternate healthy eating index (AHEI)-2010 score, anthropometric measurement, CMRF and mental health parameters were measured at Week 0 and Week 12. Albeit no major changes in CMRF observed; the control group showed increase in blood Nε-(1-carboxymethyl)-l-lysine (CML) levels, which is a well-characterized advanced glycation end product (AGE), while intervention group showed a decrease, and net changes were significantly different between groups. Additionally, the intervention group also showed decrease in depressive symptoms. Overall, no changes in dietary quality was observed. CONCLUSION: The provision of dietary counselling may be a viable nutritional strategy in regulating AGE levels and potentially reducing cardiometabolic disease risk with improving mental health in Singapore older women. REGISTRATION NUMBER OF CLINICAL TRIAL: Registered in clinicaltrials.gov as NCT03702335 and approved by the National University of Singapore Institutional Review Board (IRB H-18-040).

BACKGROUND: Dietary patterns characterized by low glycemic, minimally processed plant foods are associated with lower risk of several chronic diseases. OBJECTIVES: Evaluate the effects of a low glycemic load (LGL) compared with a high glycemic load (HGL) dietary pattern on stool bacterial community structure and metabolism. METHODS: Participants in this crossover-controlled feeding study were healthy men and women (n = 69). We identified genera, species, and genes and transcripts of metabolic pathways and bacterial enzymes using 16S rRNA gene, metagenomic and metatranscriptomic sequencing, and bioinformatic analysis. RESULTS: Overall community structure measured by alpha and beta diversity was not significantly different across the diets, although diet did significantly increase the abundance of 13 of 161 genera (Padj < 0.05) and 5 species in the LGL diet and 7 species in the HGL diet. Gene expression in the hexitol fermentation pathway (β = -1.15; SE = 0.24; 95% confidence interval [CI]: -1.63, -0.67; Padj = 0.002) was significantly higher in the HGL diet, whereas expression in the L-lysine biosynthesis pathway (β = 0.20; SE = 0.05; 95% CI: 0.09, 0.30; Padj = 0.03) was enriched in the LGL diet. The beta diversity of expressed carbohydrate-active enzymes (CAZymes) was significantly different between the diets (MiRKAT, P < 0.001). CAZymes enriched in the HGL diet reflected dietary additives, whereas CAZymes enriched in the LGL diet reflected diverse phytochemical intake. There was a significant interaction between homeostasis model assessment of insulin resistance (HOMA-IR) and the coenzyme A biosynthesis I pathway involved in bacterial fatty acid biosynthesis (Padj = 0.035), which was positive in the HGL diet (b = 0.20; SE = 0.09; 95% CI: 0.02, 0.39) and negative in the LGL diet (β = -0.23; SE = 0.09; 95% CI: -0.40, -0.06). CONCLUSIONS: In healthy humans, diet impacts microbial metabolism and enzymatic activity but not the overall diversity of the gut microbiome. This emphasizes the relevance of dietary components in activating expression of specific bacterial genes and their impact on host metabolism. This trial was registered at clinicaltrials.gov as NCT006226

Various nutritional supplements are available over the counter, yet few have been investigated in randomized controlled trials. The rationale for using the specific mix of nutritional substances including collagen type II, hyaluronic acid, n-acetyl-glucosamine, bamboo extract, L-lysine, and vitamin C is the assumption that combining naturally occurring ingredients of the intervertebral disc would maintain spine function. This double-blinded, placebo-controlled randomized trial aimed to evaluate the efficacy of a nutraceutical supplement mix in the management of lumbar osteochondrosis. Fifty patients were randomly assigned to either the supplement or placebo group in a 1:1 ratio. Patient-Reported Outcome Measures (PROMs) included the Oswestry Disability Index (ODI), the visual analogue scale for pain (pVAS), short form-12 (SF-12) physical and mental component summary subscale scores (PCS and MCS, respectively), and global physical activity questionnaire (GPAQ). Magnetic resonance imaging (MRI) was used to evaluate degenerative changes of intervertebral discs (IVD) including Pfirrmann grades as well as three-dimensional (3D) volume measurements. Data were collected at baseline and after the 3-month intervention. None of the PROMs were significantly different between the supplement and placebo groups. Disc degeneration according to Pfirrmann classifications remained stable during the 3-month intervention in both groups. Despite no significance regarding the distribution of Pfirrmann grade changes (improvement, no change, worsening; p = 0.259), in the supplement group, one patient achieved a three-grade improvement, and worsening of Pfirrmann grades were only detected in the placebo group (9.1%). Furthermore, in-depth evaluations of MRIs showed significantly higher 3D-measured volume changes (increase) in the supplement (+740.3 ± 796.1 mm3) compared to lower 3D-measured volume changes (decrease) in the placebo group (-417.2 ± 875.0 mm3; p < 0.001). In conclusion, this multi-nutrient supplement might not only stabilize the progression of lumbar osteochondrosis, but it might also potentially even increase IVD volumes as detected on MRIs.

BACKGROUND: The protein quality of wheat is limited by its low content of the indispensable amino acid (AA) lysine and the metabolic availability (MA) of lysine in wheat bread for humans is unknown. OBJECTIVES: The study objective was to determine the MA of lysine in whole wheat bread. METHODS: Five healthy young males (≤30 y, BMI <25 kg/m2) were studied in a repeated-measures design using the indicator amino acid oxidation (IAAO) method, with L-[1-13C] phenylalanine as the indicator. Each received 7 levels of lysine intakes in random order; 4 levels of L-lysine; 5, 8, 12, and 15 mg/kg/d (reference diet), and 3 intakes of lysine from whole wheat bread (test diet). The MA of lysine in whole wheat bread was assessed by comparing the IAAO response to the test diet (whole wheat bread) with the IAAO response to the reference diet using the slope ratio method. RESULTS: The MA of lysine from whole wheat bread was 90%. CONCLUSIONS: Lysine has a high MA but it is still limiting in whole wheat bread due to its low concentration. A combination of wheat with a complementary protein source (that is, lentils which are sufficient in lysine) is recommended to meet the lysine requirement in a wheat-based diet for healthy young males. This trial was registered at clinicaltrials.gov as NCT03674736 and NCT03200652.

OBJECTIVE: To evaluate the antibacterial effectiveness of a combination of ε-poly-L-lysine (ε-PL), funme peptide (FP) as well as domiphen against oral pathogens, and assess the efficacy of a BOP® mouthwash supplemented with this combination in reducing halitosis and supragingival plaque in a clinical trial. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the compound against Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans were determined by the gradient dilution method. Subsequently, the CCK-8 assay was used to detect the toxicity of mouthwash on human gingival fibroblastst, and the effectiveness in reducing halitosis and supragingival plaque of the mouthwash supplemented with the combination was analyzed by a randomized, double-blind, parallel-controlled clinical trial. RESULTS: The combination exhibited significant inhibitory effects on tested oral pathogens with the MIC < 1.56% (v/v) and the MBC < 3.13% (v/v), and the mouthwash containing this combination did not inhibit the viability of human gingival fibroblasts at the test concentrations. The clinical trial showed that the test group displayed notably lower volatile sulfur compounds (VSCs) at 0, 10, 24 h, and 7 d post-mouthwash (P < 0.05), compared with the baseline. After 7 days, the VSC levels of the and control groups were reduced by 50.27% and 32.12%, respectively, and notably cutting severe halitosis by 57.03% in the test group. Additionally, the Plaque Index (PLI) of the test and control group decreased by 54.55% and 8.38%, respectively, and there was a significant difference in PLI between the two groups after 7 days (P < 0.01). CONCLUSIONS: The combination of ε-PL, FP and domiphen demonstrated potent inhibitory and bactericidal effects against the tested oral pathogens, and the newly formulated mouthwash added with the combination exhibited anti-dental plaque and anti-halitosis properties in a clinical trial and was safe. TRIAL REGISTRATION: The randomized controlled clinical trial was registered on Chinese Clinical Trial Registry (No. ChiCTR2300073816, Date: 21/07/20

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate. © 2024 Japanese Dermatological Association.

PURPOSE: To investigate the impact of supplementation with a targeted micronutrient formulation on the visual discomfort associated with vitreous degeneration. METHODS: In this clinical trial, 61 patients with symptomatic vitreous floaters were randomized to consume daily, the active supplement consisting of 125 mg L-lysine, 40 mg vitamin C, 26.3 mg Vitis vinifera extract, 5 mg zinc, and 100 mg Citrus aurantium or placebo for 6 months. Change in visual discomfort from floaters, assessed with the Floater Disturbance Questionnaire, was the primary outcome measure. Secondary outcome measures included best-corrected visual acuity, letter contrast sensitivity, photopic functional contrast sensitivity with positive and negative contrast polarity, and quantitative vitreous opacity areas. RESULTS: After supplementation, the active group reported a significant decrease in their visual discomfort from floaters (P < 0.001), whereas the placebo group had no significant change in their visual discomfort (P = 0.416). At 6 months, there was a significant decrease in vitreous opacity areas in the active group (P < 0.001) and an insignificant increase in vitreous opacity areas in the placebo group (P = 0.081). Also, there was a significant improvement in photopic functional contrast sensitivity with positive contrast polarity in the active group after supplementation (P = 0.047). CONCLUSIONS: The findings of this study indicate improvements in vision-related quality of life and visual function of patients suffering from vitreous floaters after supplementation with a formulation of antioxidative and antiglycation micronutrients. Notably, these improvements were confirmed by the decrease in vitreous opacity areas in the active group. TRANSLATIONAL RELEVANCE: This targeted dietary intervention should be considered to support patients with symptomatic vitreous degeneration.

BACKGROUND: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. METHODS: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18-50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. FINDINGS: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months

The clinical therapeutic effect of immune-checkpoint blockade (ICB) on triple-negative breast cancer (TNBC) is limited due to low tumor immunogenicity and tumor immunosuppressive microenvironment. Combination therapies of chemotherapy and ICB have been confirmed efficacious. Herein, poly(L-lysine) dendrimer (PLLD) nanosphere (PR-T@PLLD) integrating chemotherapeutic drug paclitaxel (PTX), natural anti-tumor compound Rubioncolin C (RC) and TIGIT/PVR blocking peptide DTBP-3 is constructed for chemo-immunotherapy of anti-PD-1 resistant tumor. The PEGylation and DTBP-3 modification endow PR-T@PLLD with prolonged blood circulation, enhanced tumor penetration and improved internalization. In the acidic environment of lysosomes, PR-T@PLLD disassembles and releases PTX, RC and DTBP-PLLD. The cell death induced by PTX is significantly enhanced through synergy with RC. RC collaborated PTX also triggers robust immunogenic cell death that efficiently increases tumor infiltration of cytotoxic T lymphocytes (CTLs). Additionally, the released DTBP-PLLD inhibits the exhaustion of CTLs via directly binding to TIGIT and blocking the interaction of TIGIT with its ligand PVR. Thus, PR-T@PLLD arouses a conspicuous anti-tumor immune response via increasing income and reducing expenditure of CTLs. Moreover, PR-T@PLLD reduces the recruitment of immunosuppressive cells in tumor. PR-T@PLLD also inhibits tumor metastasis through evoking immune memory response and inhibiting epithelial-mesenchymal transition and extracellular matrix degradation. In general, PR-T@PLLD is a promising nanoplatform realizing synergistic enhancement of chemo-immunotherapy against anti-PD-1 resistant TNBC. © 2025. The Author(s).

BACKGROUND: A previous study indicated that poly L-lysine-glycerol monolaurate mouthwash reduced the virulence of Helicobacter pylori; however, these compounds are derivatives. Thus, this study aimed to compare the effects of postbiotics, postbiotic-glycerol monolaurate, and poly L-lysine-glycerol monolaurate mouthwashes against clinical H. pylori strains. METHODS: Postbiotics, Lacticaseibacillus paracasei SD1, L. rhamnosus SD4, and L. rhamnosus SD11 were examined for anti-bacterial activity and synergistic effects. Subsequently, mouthwashes containing postbiotics, postbiotic-glycerol monolaurate, and poly L-Lysine-glycerol monolaurate were prepared and evaluated for their ability to reduce H. pylori adhesion to host cells, suppress inflammation induced by H. pylori, eradicate biofilm, decrease cagA expression, and assess epithelial cell viability. The stability of the mouthwashes was evaluated every 4 weeks up to 24 weeks for their efficacy against H. pylori growth, biofilm eradication, and epithelial cell viability. RESULTS: The postbiotics, L. paracasei SD1 and L. rhamnosus SD11, demonstrated significant anti-H. pylori activity, with synergistic effects observed in combinations with derivative compounds. Postbiotic-glycerol monolaurate mouthwashes exhibited higher efficacy in reducing H. pylori adhesion to host cells (42.64-43.83%), suppressing pro-inflammatory cytokines, eradicating biofilm (82.62% at 24 h), and reducing cagA expression (112.60 fold) compared to others. Such mouthwashes also displayed low cytotoxicity (< 30% for 15 min) to all cells tested. The stability was observed up to 24 weeks. CONCLUSION: This in vitro study demonstrated that postbiotic-glycerol monolaurate mouthwash revealed the highest efficacy against H. pylori with low cytotoxicity to host cells. The stability lasted for 24 weeks.

Multidrug-resistant P. aeruginosa (MDR-P. aeruginosa), associated with elevated morbidity, mortality, and readmission rates, presents a formidable challenge to eradication due to its robust resistance to antimicrobial agents and biofilm formation. Herein, self-assembling nanoparticles (NO-PE/PLL NPs) comprised of NO donor-conjugated γ-polyglutamic acid (GSNO-PGA), epsilon-poly-l-lysine (PLL) and colistin were fabricated. The negatively charged NO-PE/PLL NPs exhibited effective penetration through airway mucus, reaching the infection site where GSNO-PGA released NO in response to glutathione within biofilm. PLL worked synergistically with colistin (fractional inhibitory concentration index: 0.281), reducing the minimum inhibitory concentration (MIC) of colistin from 2 to 0.5 μg/mL. Benefiting from this synergistic antibacterial action and NO-mediated biofilm disruption, NO-PE/PLL NPs achieved a 99.99 % eradication rate against MDR-P. aeruginosa biofilms. Additionally, NO-PE/PLL NPs efficiently inhibited endotoxins-stimulated inflammation response. In a chronic pulmonary infection model, NO-PE/PLL NPs displayed the highest eradication efficiency (99.78 %) to infected mice, while having no adverse effects on their major organs or pulmonary functions. These results highlight NO-PE/PLL NPs as a promising therapeutic strategy for treating recalcitrant infections caused by MDR-P. aeruginosa biofilms.

This study investigated the synergistic effects of ε-poly- L -lysine (ε-PL) and lysozyme against P. aeruginosa and L. monocytogenes biofilms. Single-culture biofilms of two bacteria were formed on silicone rubber (SR), stainless steel (SS), and beef surfaces and then treated with lysozyme (0.05-5 mg/mL) and ε-PL at minimum inhibitory concentrations (MICs) of 1 to 4 separately or in combination. On the SR surface, P. aeruginosa biofilm was reduced by 1.4 and 1.9 log CFU/cm2 within 2 h when treated with lysozyme (5 mg/mL) and ε-PL (4 MIC), respectively, but this reduction increased significantly to 4.1 log CFU/cm2 (P < 0.05) with the combined treatment. On beef surface, P. aeruginosa and L. monocytogenes biofilm was reduced by 4.2-5.0, and 3.3-4.2 log CFU/g when lysozyme was combined with 1, 2, and 4 MIC of ε-PL at 25 °C, respectively. Compared to 5 mg/mL lysozyme alone, the combined treatment with 1, 2, and 4 MIC of ε-PL on beef surface achieved additional reduction against P. aeruginosa biofilm of 0.5, 0.8, and 0.7 log CFU/g, respectively, at 25 °C. In addition, 0.25 mg/mL lysozyme and 0.5 MIC of ε-PL significantly (P < 0.05) suppressed the quorum-sensing (agrA) and virulence-associated (hlyA and prfA) genes of L. monocytogenes.

BACKGROUND: Doxorubicin (DOX) is a chemotherapy drug that is widely used in cancer therapy, especially in Triple-Negative Breast Cancer (TNBC) patients. Nevertheless, cytoprotective autophagy induction by DOX limits its cytotoxic effect and drug resistance induction in patients. Therefore, finding a new way is essential for increasing the effectiveness of this drug for cancer treatment. OBJECTIVE: This study aimed to investigate the effect of L-lysine on DOX cytotoxicity, probably through autophagy modulation in TNBC cell lines. METHODS: We used two TNBC cell lines, MDA-MB-231 and MDA-MB-468, with various levels of autophagy activity. Cell viability after treatment with L-lysine alone and in combination therapy was evaluated by MTT assay. Reactive Oxygen Species (ROS), nitric oxide (NO) concentration, and arginase activity were assessed using flow cytometric analysis, Griess reaction, and arginase activity assay kit, respectively. Real-time PCR and western blot analysis were used to evaluate the L-lysine effect on the autophagy-related genes and protein expression. Cell cycle profile and apoptotic assay were performed using flow cytometric analysis. RESULTS: The obtained data indicated that L-lysine in both concentrations of 24 and 32 mM increased the autophagy flux and enhanced the DOX cytotoxicity, especially in MDA-MB-231, which demonstrated higher autophagy activity than MDA-MB-468, by inducing ROS and NO production. Furthermore, L-lysine induced G2/M arrest autophagy cell death, while significant apoptotic changes were not observed. CONCLUSION: These findings suggest that L-lysine can increase DOX cytotoxicity through autophagy modulation. Thus, L-lysine, in combination with DOX, may facilitate the development of novel adjunct therapy for cancer.

Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital- and community-acquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) and a Gram-positive bacterium (Mycobacterium smegmatis) to aminoglycosides. Importantly, the combination of L-lysine with aminoglycosides killed clinically isolated multidrug-resistant Acinetobacter baumannii and persister cells. The exogenous L-lysine can increase proton motive force via transmembrane chemical gradient, resulting in aminoglycoside acumination that further accounts for reactive oxygen species production. The combination of L-lysine and antibiotics highlights a promising strategy against bacterial infection.

The emergence of drug-resistant fungal strains remains a severe threat for the public health, which prompts strict restrictions on the uses of antifungal drugs. However, the majority of lipophilic fungistatic agents are poorly water soluble with a low oral adsorption characteristic posing challenges for the precise prescriptions. In this study, a natural antimicrobial cationic peptide of epsilon-poly-l-lysine (EPL) decorated ordered mesoporous silica (SBA-15) was facilely prepared for the efficient loading of antifungal itraconazole (ITZ) drugs. The characterized mesoporous SBA-15/EPL/ITZ composite exhibited remarkable antifungal performance against Aspergillus fumigatus as a model mold, which was attributed to synergistic antifungal activities of ITZ and EPL in the mesopores. Moreover, the in vitro release behaviors of ITZ in the composite nanoexcipients both in simulated gastric fluid and fasted state simulated intestinal fluid were studied. The observed release kinetics of ITZ demonstrated a contributing role of SBA-15/EPL to enhance the solubility of ITZ and thereby may promote its flux across the gastrointestinal epithelium, which is beneficial for the absorption of drugs. Additionally, SBA-15/EPL/ITZ composites showed desirable biocompatibility toward mammalian red blood cells, human cervical cancer cells (Hela) and human embryonic kidney cells (HEK-293T). Furthermore, the pharmacokinetic profiles of obtained nano-formulations were assessed in rats, among which the improved adsorption of SBA-15/EPL/ITZ composites (AUC0-24h sum: 8381.7 nM·h) was identified compared with that of pure ITZ (525.1 nM·h) and the commercial drug of Sporanox (7516.6 nM·h). Collectively, the prepared SBA-15/EPL/ITZ provides an ecofriendly and integrated nanocomposite with enhanced solubility of lipophilic drugs to combat proliferations of infectious fungi.

AIM: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. MATERIALS AND METHODS: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. RESULTS: Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. CONCLUSION: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.

BACKGROUND: In vitro systems allowing maintenance and experimentation on primary astrocyte cultures have been used for decades. Astrocyte cultures are most maintained in serum-containing medium which has been found to alter the morphology and gene profiles of astrocytes. NEW METHOD: Here, we reported a new serum-free medium for astrocyte culture, which consisted of DMEM and NB media supplemented with insulin and heparin-binding epidermal growth factor-like growth factor (HB-EGF) (SF-I-H medium). Meanwhile FBS-containing (FBS) medium composed of DMEM medium containing 10% FBS were used for comparison study. Cerebral cortex was harvested from postnatal day 1 Wistar rats and brain cells were isolated and seeded to poly-L-lysine coated culture dishes after 15 min differential velocity adherence. RESULTS: Compared with FBS medium, astrocytes in SF-I-H medium were smaller and exhibited process bearing morphologies. MTT assays showed that cell density and proliferation rate were higher in SF-I-H medium than in FBS medium all the time, and flow cytometry analysis revealed that SF-I-H medium promoted cell mitosis in a manner comparable to FBS medium. Consistently, western blot analysis further revealed that insulin and HB-EGF synergistically activated the PI3K/AKT and MAPK/ERK1/2 signaling cascades as FBS. COMPARISON WITH EXISTING METHOD(S): Astrocytes cultured in SF-I-H medium grew faster than FBS medium. CONCLUSION: Taken together, our results indicated that SF-I-H medium, in which cell morphology was similar with astrocytes in brain, was more effective for astrocyte survival and proliferation than FBS medium, providing a new cell model to study astrocyte functions without the interference of serum.

The antifungal properties and the induction of resistance by ε-poly-l-lysine (ε-PL) and chitooligosaccharide (COS) were examined to find an alternative to synthetic fungicides currently used in the control of the devastating fungal pathogen Botrytis cinerea, the causal agent of grey mould disease of tomatoes. As presented herein, this combined treatment (200 mg/L ε-PL + 400 mg/L COS) was found to have optimal in vitro antifungal activities, achieving an inhibition rate of 90.22%. In vivo assays with these combined bio-fungicides, under greenhouse conditions using susceptible tomato plants, demonstrated good protection against severe grey mould. In field tests, the combined bio-fungicides had a control effect of up to 66.67% against tomato grey mould. To elucidate the mechanisms of the combined bio-fungicide-induced resistance in the tomato, plants were subjected to three treatments: 1) inoculation with B. cinerea after spraying with 200 mg/L ε-PL alone, 2) inoculation with the combined bio-fungicides, and 3) inoculation with 400 mg/L COS alone. Compared to the control (sterile water), increases in salicylic acid (SA) and jasmonic acid (JA) levels and increased phenylalanine ammonia lyase (PAL), peroxidase (POD), and superoxide dismutase (SOD) activities were observed. Catalase (CAT) activity and abscisic acid (ABA) and gibberellin (GA) levels decreased, particularly in the combined bio-fungicide-treated plants. Altogether, these findings reveal that the combined bio-fungicides (200 mg/L ε-PL + 400 mg/L COS) should be an excellent biocontrol agent candidate that combines direct antifungal activity against B. cinerea with plant resistance.

PURPOSE: Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with diabetes still develop DR despite appropriate glycemic and blood pressure control, highlighting the pressing need to identify useful biomarkers for risk stratification. The purpose of this review is to systematically summarize potential metabolic biomarkers and pathways of DR, which could facilitate developing an understanding of the disease mechanisms, as well as new therapeutic measures. METHODS: We searched PubMed and Web of Science for relevant metabolomics studies on humans published before September 30, 2020. Information regarding authors, title, publication date, study subjects, analytical platforms, methods of statistical analysis, biological samples, directions of change of potential metabolic biomarkers, and predictive values of metabolic biomarker panels was extracted, and the quality of the studies was assessed. Pathway analysis, including enrichment analysis and topology analysis, was derived from integrating differential metabolites using MetaboAnalyst 3.0, based on the Kyoto Encyclopedia of Genes and Genomes and Human Metabolome Database. RESULTS: We found nine studies focused on the identification of potential biomarkers. Repeatedly identified metabolites including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid were found to be potential biomarkers of DR. It was observed that l-glutamine and citrulline changed in all biological samples. Dysregulation of metabolic pathways involved amino acid and energy metabolism. CONCLUSIONS: This review summarizes potential biomarkers and metabolic pathways, providing insights into new pathogenic pathways for this microvascular complication of diabetes.

Gyrate atrophy of the choroid and retina (GACR) is a rare inborn error of amino acid metabolism caused by bi-allelic variations in OAT. GACR is characterised by vision decline in early life eventually leading to complete blindness, and high plasma ornithine levels. There is no curative treatment for GACR, although several therapeutic modalities aim to slow progression of the disease by targeting different steps within the ornithine pathway. No international treatment protocol is available. We systematically collected all international literature on therapeutic interventions in GACR to provide an overview of published treatment effects. METHODS: Following the PRISMA guidelines, we conducted a systematic review of the English literature until December 22nd 2020. PubMed and Embase databases were searched for studies related to therapeutic interventions in patients with GACR. RESULTS: A total of 33 studies (n = 107 patients) met the inclusion criteria. Most studies were designed as case reports (n = 27) or case series (n = 4). No randomised controlled trials or large cohort studies were found. Treatments applied were protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, l-lysine supplementation, and proline supplementation. Protein-restricted diets lowered ornithine levels ranging from 16.0-91.2%. Pyridoxine responsiveness was reported in 30% of included mutations. Lysine supplementation decreased ornithine levels with 21-34%. Quality assessment showed low to moderate quality of the articles. CONCLUSIONS: Based primarily on case reports ornithine levels can be reduced by using a protein restricted diet, pyridoxine supplementation (variation-dependent) and/or lysine supplementation. The lack of pre-defined clinical outcome measures and structural follow-up in all included studies impeded conclusions on clinical effectiveness. Future research should be aimed at 1) Unravelling the OAT biochemical pathway to identify other possible pathologic metabolites besides ornithine, 2) Pre-defining GACR specific clinical outcome measures, and 3) Establishing an international historical cohort.

Different amino acids (AAs) may exert distinct effects on postprandial glucose and insulin concentrations. A quantitative comparison of the effects of AAs on glucose and insulin kinetics in humans is currently lacking. PubMed was queried to identify intervention studies reporting glucose and insulin concentrations after acute ingestion and/or intravenous infusion of AAs in healthy adults and those living with obesity and/or type 2 diabetes (T2DM). The systematic literature search identified 55 studies that examined the effects of l-leucine, l-isoleucine, l-alanine, l-glutamine, l-arginine, l-lysine, glycine, l-proline, l-phenylalanine, l-glutamate, branched-chain AAs (i.e., l-leucine, l-isoleucine, and l-valine), and multiple individual l-AAs on glucose and insulin concentrations. Oral ingestion of most individual AAs induced an insulin response, but did not alter glucose concentrations in healthy participants. Specific AAs (i.e., leucine and isoleucine) co-ingested with glucose exerted a synergistic effect on the postprandial insulin response and attenuated the glucose response compared to glucose intake alone in healthy participants. Oral AA ingestion as well as intravenous AA infusion was able to stimulate an insulin response and decrease glucose concentrations in T2DM and obese individuals. The extracted information is publicly available and can serve multiple purposes such as computational modeling.

BACKGROUND: Despite the widespread use of l-lysine in dietary supplements, the safety information pertinent to excessive l-lysine ingestion is limited and, to the best of our knowledge, there is no published systematic review of safety. OBJECTIVE: The objective of this study was to assess the clinical safety of l-lysine supplementation of a regular diet. METHODS: We searched PubMed, Cochrane Library, Ichushi Web, and EBSCOhost using the relevant keywords, "l-lysine" and "clinical trial." To investigate all adverse events observed during intervention trials, we included all intervention studies with orally ingested l-lysine without restricting background factors, environment, study designs, and sample sizes. RESULTS: We identified 71 articles, which included 3357 study subjects. The l-lysine doses ranged from 16.8 to 17.5 g/d, and the dosing period ranged from 1 to 1095 d. The observed adverse events were mainly subjective gastrointestinal tract symptoms; however, the risk analysis for incidence of gastrointestinal symptoms was not statistically significant (risk ratio of 1.02). CONCLUSION: The provisional no-observed-adverse-effect level in healthy human subjects was based on gastrointestinal symptoms and identified at 6.0 g/d. The review protocol was registered at umin.ac.jp as UMIN000028914 before the beginning of the study. © The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.

Currently, the use of amino acids in supplements and functional foods is increasing globally. However, there are no guidelines for the upper limit of ingestion for the safe use of these amino acids. Safety evaluation of chemical substances is generally performed through non-clinical and clinical studies. However, amino acids that have these safety data are limited. Therefore, we used a systematic review approach for evaluating the safety of amino acids. In the present study, we evaluated the safety of L-lysine added to an ordinary diet in humans. Using PubMed, Cochrane Library, Ichushi Web, and EBSCOhost as search databases, we comprehensively searched human studies on oral ingestion of L-lysine. Ultimately, 71 studies were selected for evaluation. Of these, 12 studies were of relatively high quality with Jadad scores ≥ 3. The dose range of L-lysine in the selected studies was 16.8-17,500 mg/day, and the range of dosing period was 1-1095 days. The observed adverse events were mainly subjective symptoms related to the gastrointestinal tract such as nausea, stomachache, and diarrhea. The provisional no-observed-adverse-effect level obtained based on these gastrointestinal symptoms was 6000 mg/person/day. Integrated analysis of the risk for developing gastrointestinal symptoms revealed that the risk ratio was 1.02 (95% CI, 0.96-1.07; p = 0.49); thus, no significant increase was observed. (UMIN000028914).

BACKGROUND: Over the past several decades, complementary and alternative medications have increasingly become a part of everyday treatment. With the rising cost of prescription medications and their production of unwanted side effects, patients are exploring herbal and other natural remedies for the management and treatment of psychological conditions. Psychological disorders are one of the most frequent conditions seen by clinicians, and often require a long-term regimen of prescription medications. Approximately 6.8 million Americans suffer from generalized anxiety disorder. Many also suffer from the spectrum of behavioural and physical side effects that often accompany its treatment. It is not surprising that there is universal interest in finding effective natural anxiolytic (anti-anxiety) treatments with a lower risk of adverse effects or withdrawal. METHODS: An electronic and manual search was performed through MEDLINE/PubMed and EBSCO. Articles were not discriminated by date of publication. Available clinical studies published in English that used human participants and examined the anxiolytic potential of dietary and herbal supplements were included. Data were extracted and compiled into tables that included the study design, sample population, intervention, control, length of treatment, outcomes, direction of evidence, and reported adverse events. RESULTS: A total of 24 studies that investigated five different CAM monotherapies and eight different combination treatments and involved 2619 participants met the inclusion criteria and were analyzed. There were 21 randomized controlled trials and three open-label, uncontrolled observational studies. Most studies involved patients who had been diagnosed with either an anxiety disorder or depression (n = 1786). However, eight studies used healthy volunteers (n = 877) who had normal levels of anxiety, were undergoing surgery, tested at the upper limit of the normal range of a trait anxiety scale, had adverse premenstrual symptoms or were peri-menopausal, reported anxiety and insomnia, or had one month or more of elevated generalized anxiety. Heterogeneity and the small number of studies for each supplement or c

Following traumatic brain injury (TBI), secondary injury driven by iron-dependent lipid peroxidation (ferroptosis) causes permanent neurological deficits. Although Ghrelin exhibits neuroprotective properties, its role in regulating ferroptosis post-TBI remains unclear. This study aimed to investigate the effects of Ghrelin on neurological function after TBI and to elucidate the underlying mechanisms. A mouse TBI model was established by controlled cortical impact (CCI), and Ghrelin was intraperitoneally administered at 1h before and 1h after CCI induction. The results showed that Ghrelin improved neurological deficits, brain edema, and histopathological damage in TBI mice. In addition, Ghrelin reversed the TBI-induced accumulation of Fe²⁺, reactive oxygen species (ROS), and malondialdehyde (MDA), and restored superoxide dismutase (SOD) and glutathione (GSH) levels. At the molecular level, Ghrelin downregulated acyl-CoA synthetase long-chain family member 4 (ACSL4) and upregulated ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4). These effects were abolished by co-administration of the ferroptosis inducer Erastin. In the brain tissue of TBI mice, Ghrelin reversed the TBI-induced downregulation of lysine-specific demethylase 1 (LSD1), specificity protein 1 (Sp1), and p62 expression. Consistently, in vitro experiments showed that Ghrelin attenuated Erastin-induced ferroptosis in the mouse hippocampal neuronal cell line HT22 and increased L

GHK-Cu, the copper-bound form of the human tripeptide glycyl-L-histidyl-L-lysine has accumulated more than four decades of pre-clinical evidence for tissue regeneration, anti-inflammatory action, antioxidant capacity, and broad gene-expression remodeling. Yet despite this volume, the clinical literature in humans remains thin and fragmented: most randomized trials are small, conducted on facial cosmetic creams, and rarely paired with delivery technologies capable of reliably crossing the stratum corneum. The microneedle-mediated delivery route which has been shown in vitro and in porcine ex vivo models to dramatically enhance GHK-Cu skin uptake has yet to be evaluated in a single registered, adequately powered human randomized controlled trial published in the peer-reviewed literature. This systematic review synthesizes the body of GHK-Cu literature published between 2005 and 2026, mapped against the PRISMA framework. Searches across PubMed, Elsevier ScienceDirect, and the Cochrane CENTRAL Registry yielded 1,247 records; after deduplication and screening, 64 records were retained for qualitative synthesis. Studies were stratified by study model (in vitro, ex vivo, in vivo rodent, in vivo non-rodent, and human) so that comparator therapies could be matched on equivalent footing. A critical discussion is provided on the physiology and underlying mechanistic foundation of GHK-Cu activity, including its role as an endogenous matricryptin released from collagen Iα2 and SPARC, copper's essential cofactor function for the lysyl oxidase family of cross-linking enzymes, decorin and glycosaminoglycan organization of ne

Abnormal iron metabolism and ferroptosis contribute to diabetic cardiomyopathy (DCM); however, the regulatory mechanisms remain unclear. Inulin improves systemic metabolism and cardiac function, but whether it alleviates myocardial ferroptosis and DCM is unknown. Using two distinct type 2 diabetes (T2D) mouse models-the high-fat diet combined with streptozotocin-induced T2D model and the db/db mouse model-in combination with an iron chelator, we found that imbalanced iron homeostasis and ferroptosis drive DCM. Inulin restored cardiac iron homeostasis, inhibited ferroptosis and DCM, and promoted short-chain fatty acids (SCFAs). Treatment with an SCFA inhibitor confirmed that SCFAs mediate the cardioprotective effects of inulin, with butyrate exerting the most potent antiferroptotic effect. Hypoxia-inducible factor 1α (HIF-1α) expression was decreased in DCM, and bioinformatic analysis identified HIF-1α as a hub gene in ferroptosis. Interference with HIF-1α in the two distinct T2D mouse models and in vitro weakened the antiferroptotic effect of butyrate. Mechanistically, butyrate inhibited HIF-1α ubiquitination by inducing HIF-1α butyrylation at lysine 190, which upregulated transcription of ferritin heavy chain (FTH) and mitochondrial ferritin (FTMT) to enhance the storage of unstable iron. HIF-1α acts as a critical regulator of myocardial iron homeostasis through transcriptional upregulation of FTH/FTMT. Inulin-fermented butyrate prevents ferroptosis-driven DCM, and its protective effect depends on the HIF-1α-FTH/FTMT axis via butyrylation. These findings highlight the therapeutic potential of using inulin or target

BACKGROUND: Biotinidase is an enzyme recycling endogenous biotin by hydrolyzing ε-N-biotinyl lysine (biocytin) to lysine and biotin. Biotin acts as a coenzyme in various carboxylation reactions. Biotinidase deficiency is rare, with an incidence of 1 per 112,271 individuals. OBJECTIVES: Genetic characterization of a 4-month-old boy born out of a consanguineous marriage presented with cutaneous manifestations, alopecia, developmental delay, hypotonia with absent neck holding, respiratory problems, and biotinidase deficiency. METHODS: Biochemical characterization was performed using tandem mass spectrometry and immunofluorescence enzyme assays. Pathogenic genetic variant was identified by Sanger sequencing of the BTD (biotinidase) gene in a patient and his parents. RESULTS: Biochemical characterization indicated elevated methylmalonylcarnitine/hydroxyisovalerylcarnitine and decreased biotinidase, citrulline, glycine, and ornithine levels, suggesting a profound biotinidase deficiency. Sequencing of BTD gene indicates the presence of a 7-bp deletion and a 3-bp insertion (98-104del7ins3) in a homozygous state, resulting in a change of amino acid from cystine to phenylalanine at the 33rd position, causing a frameshift and premature amino acid termination at the 68th position. CONCLUSIONS: A 7-bp deletion and a 3-bp insertion (98-104del7ins3) homozygous variation in the BTD gene segregating in a homozygous recessive manner in the family, causing truncated, nonfunctional biotinidase deficiency in the proband. This is a recurrent mutation and has the potential to be used as a biomarker for screening patients with biotinidase deficiency.

OBJECTIVE: Wiedemann-Steiner syndrome (WSS) is a neurodevelopmental disorder caused by pathogenic KMT2A variants and characterized by intellectual disability, behavioral challenges, and executive dysfunction. KMT2A loss has been linked to atypical neurogenesis in hippocampal and prefrontal regions, potentially contributing to dysregulated behaviors. Endocrinological abnormalities have also been found among those with WSS, which in turn may impact their stress biology. This study examines the associations between chronic stress, measured by hair cortisol concentration (HCC), and cognitive and behavioral functioning in WSS. METHOD: Twenty White individuals with WSS (14 female; Mage = 14.85 years, SD = 6.14) completed standardized tests of executive functioning. Caregivers completed the Behavior Rating Inventory of Executive Function and the Child/Adult Behavior Checklist to index daily behavior functioning. Hair samples were collected from participants and their parents to derive HCC. RESULTS: Mean HCC levels in the subset of children with WSS did not differ from normative reference values. In our whole cohort, higher HCC was associated with poorer performance scores on tests of cognitive flexibility. Regression models showed that higher HCC predicted poorer cognitive flexibility, explaining 36%-42% of the variance. CONCLUSIONS: These findings provide preliminary evidence that long-term cortisol levels are related to performance-based executive functioning difficulties in WSS. Results within the context of extant literature on WSS suggest that altered stress physiology, such as chronic exposure to stress hormone production, may contribute to their executive and behavioral dysfunction,

Iron overload disrupts cellular homeostasis and drives ferroptosis through dysregulated iron metabolism. Non-coding RNAs (ncRNAs) are considered as key regulators of various biological functions and targets for a new generation of RNA therapeutics and biomarkers. However, few studies have investigated the regulatory roles of ncRNAs, particularly competitive endogenous RNAs (ceRNAs) in iron overload. This study performed whole-transcriptome sequencing to characterize the ceRNA network in ferric ammonium citrate (FAC)-induced iron-overloaded HT-1080 fibrosarcoma cells. A total of 208 differentially expressed mRNAs, 83 lncRNAs, and 170 circRNAs (q < 0.05) were identified, with hierarchical clustering revealing distinct expression patterns between control and iron-treated groups. KEGG enrichment implicated vitamin B6 metabolism (q < 0.001) and lysine degradation (q < 0.001) as key disrupted pathways. ceRNA network was conducted and further demonstrated lncRNA/circRNA-mediated regulation of ferroptosis genes via shared miRNA response elements. Notably, LINC-PINT-232 was implicated in the regulation of both ferritin heavy chain (FTH) and sequestosome 1 (SQSTM1), two ferroptosis-associated mRNAs. FTH upregulation mitigates iron toxicity through ferroxidase activity, while SQSTM1 modulates lipid peroxidation in ferroptosis. These findings provide a preliminary transcriptomic landscape for hypothesis generation regarding ncRNA-mediated regulatory mechanisms in iron overload-induced ferroptosis and offer a computational foundation for future functional and therapeutic investigations.

CLINICAL CHARACTERISTICS: The phenotypic spectrum of untreated glutaric acidemia type 1 (GA1) ranges from severe dystonia due to basal ganglia injury to a variety of other later-onset neurologic manifestations to asymptomatic individuals. The GA1 phenotype can vary widely among untreated family members with the same genotype, primarily as a function of the timing and severity of acute basal ganglia injury. Acute early-onset injury may occur from age three months to three years in infantile-onset GA1 (rarely, up to age six years); more insidious neurologic manifestations may occur after age six years in late-onset GA1. Acute injury manifests as acute bilateral striatal injury and subsequent complex movement disorders. Affected individuals may also develop insidious-onset basal ganglia injury in the absence of an identified acute encephalopathic crisis. Infants identified by newborn screening (NBS) and started on treatment may not develop basal ganglia injury or subsequent movement disorder. Extrastriatal symptoms may occur after age six years including neurologic sequelae such as epilepsy, stroke, and cerebral palsy-like manifestations. DIAGNOSIS/TESTING: The diagnosis of GA1 can be established in a proband with suggestive findings and biallelic pathogenic variants in GCDH identified by molecular genetic testing or significantly reduced glutaryl-CoA dehydrogenase enzyme activity in cultured fibroblasts or leukocytes. MANAGEMENT: Targeted therapies: When GA1 is suspected during the diagnostic evaluation of a newborn with an elevated concentration of 3-hydroxyglutaric acid (3-OH-GA) in plasma or urine, metabolic treatment should be initiated immediately, including avoiding catabolism, a low-lysine diet, and carnitine supplementatio

Age-related hearing loss (ARHL) is a growing global health concern due to its irreversibility and multifactorial pathogenesis. Epigenetic alterations are emerging as key drivers of aging, yet the mechanisms underlying their contribution to ARHL remain poorly understood. Here, we identified the histone H3 lysine 9 dimethylation (H3K9me2)-forkhead box G1 (FOXG1)-microRNA axis as a crucial regulator of auditory degeneration through modulation of autophagy. Using in vivo and in vitro D-galactose-induced aging models, we observed that H3K9me2 levels exhibited an inverse relationship with FOXG1 expression in cochlear hair cells. FOXG1 regulated autophagy by controlling autophagy-related microRNAs, thereby modulating reactive oxygen species accumulation and apoptosis in aging hair cells. Furthermore, a multi-omics

Histone H3K9me3 silences repetitive elements and represses non-lineage genes during early development, but its role in organogenesis is understudied. Here, we show that H3K9me3 deposition is dynamic during epidermis morphogenesis and essential for lineage diversification. We ablate Suv39h1, Suv39h2, and Setdb1 histone methyltransferases, in the embryonic mouse epidermis, to induce H3K9me3 loss. This causes complete failure of keratinocyte differentiation, skin barrier formation, hair follicle development, and Merkel cell specification. Single-cell transcriptomics reveals aberrant cell fates with mixed epidermal subtype identities and dysregulated non-lineage and lineage-specific transcription programs. Affected pathways include differentiation, metabolism, cell cycle, cytoskeletal organization, and extracellular matrix. H3K9me3 primarily restricts RNA Pol II transcription initiation at key developmental promoters and enhancers and has minimal direct effect on promoter-proximal pause release. We uncover a cooperative and indispensable role for Suv39h1, Suv39h2, and Setdb1 in gene expression control of epidermal morphogenesis, establishing H3K9me3 as a critical developmental determinant of skin organogenesis. © 2026. The Author(s).

Age-related hearing loss (ARHL) is a prevalent sensory deficit characterized by cochlear hair cell apoptosis, yet the underlying epigenetic mechanisms remain unclear. This study investigated the role of E2F1-mediated 53BP2 lactylation in ARHL pathogenesis using naturally aging C57BL/6J mice and HEI-OC1 cochlear hair cell-like cells. We found that E2F1 was significantly upregulated in aged cochleae, correlating with elevated ABR thresholds, hair cell loss, and apoptotic marker expression. In vitro, E2F1 overexpression promoted HEI-OC1 cell apoptosis by stabilizing p53, while E2F1 knockdown attenuated p53 accumulation and cell death under oxidative stress. Mechanistically, mass spectrometry identified 53BP2 lactylation at lysine 476 (K476), which was enhanced by E2F1. The K476R mutation abolished 53BP2-p53 binding, reduced p53 stability, and inhibited apoptosis. Further, E2F1 transcriptionally upregulated p300, a lactyltransferase that directly mediates 53BP2 K476 lactylation. p300 knockdown reversed E2F1-induced 53BP2 lactylation and p53-dependent apoptosis. These findings reveal a novel E2F1-p300-53BP2 lactylation-p53 signaling axis driving cochlear hair cell apoptosis in ARHL, highlight

This study evaluated effects of a nutrient-enriched late gestation diet (LGPHASE) on reproductive performance and blood-based biomarkers in sows and their progeny through weaning. Seventy sows (parity 0-5) at 70 ± 2 d gestation were assigned to a control (CON; n = 35; 11% CP, 0.52% SID lysine, industry-standard organic trace minerals, and vitamins) or a LGPHASE diet (n = 35; 16% CP, 0.87% SID lysine, 2 × CON industry-standard organic trace minerals and vitamins except selenium, plus 500 mg/kg vitamin C) fed from days 70 to 110 of gestation. All sows received a common lactation diet. Blood was collected from sows at day 70 ± 2, day 110 ± 2, and weaning (lactation day 19 ± 3) for blood counts and serum analysis. Piglet Hb was measured at birth (CON: n = 479; LGPHASE: n = 495) and at weaning (CON: n = 395; LGPHASE: n = 431), and serum was collected from 2 piglets per litter (n = 70 per treatment) at 40-48 h post farrow and weaning. Sow and piglet serum was analyzed for copper, iron, zinc, ferritin, and 25(OH)D3. Farrowing duration was shorter in LGPHASE than CON sows (290.4 vs. 359.9 min; P = 0.028). Litter size and birth weight were similar between treatments, however, a reduced stillbirth rate tended to occur in LGPHASE sows (3.4% vs. 6.8%; P = 0.099). LGPHASE sows tended to wean more (13.4 vs. 12.3; P = 0.062) and lighter pigs (5.70 vs. 6.16 kg; P = 0.087) with increased piglet survivability (90.5% vs. 84.8%; P = 0.019). LGPHASE sows tended to have higher Hb at day 110 (11.2 vs. 1

N1-methyladenosine (m1A) modification widely occurs in various RNAs, yet its pathophysiological function in tumorigenesis remains poorly understood. Notably, the expression and biological roles of tRNA m1A methyltransferase 6 noncatalytic subunit (TRMT6) in breast cancer, particularly in triple-negative breast cancer (TNBC), are unknown. Herein, it is demonstrated that TRMT6 is markedly elevated in TNBC, due to the H3K4me3 methylation modification occurring at the promoter region to enhance transcription. Through integrated analyses of m1A tRNA methylated RNA immunoprecipitation sequencing, ribosome profiling sequencing, RNA sequencing and data-independent acquisition mass spectrometry, ferritin heavy chain 1 (FTH1) is identified as a downstream target of TRMT6. Mechanistically, it is found that TRMT6 is responsible for the formation of m1A methylation on tRNAs, which increases the translation efficiency of FTH1. Besides, TRMT6 promotes ferritin light chain (FTL) expression at both transcriptional and translational levels, further reinforcing its role in iron met