Glutathione

Glutathione (GSH), the most abundant intracellular antioxidant, plays a central role in maintaining redox homeostasis, regulating immune responses, and protecting cellular integrity. In chronic diseases such as type 2 diabetes mellitus (T2DM), GSH deficiency is a consistent hallmark, contributing to oxidative stress, mitochondrial dysfunction, inflammation, and progressive organ damage. This review critically examines the efficacy and safety of GSH supplementation and precursor strategies, synthesizing evidence across mechanistic studies, clinical trials, and translational research. In T2DM, GSH augmentation has been linked to improved insulin sensitivity, reduced oxidative damage, and better microvascular outcomes, although findings remain preliminary and heterogeneous. Safety profiles across populations are highly favorable, with gastrointestinal discomfort being the most reported adverse effect and serious toxicities rare. Importantly, both acute and chronic studies reinforce the compatibility of GSH and its precursors with standard antiretroviral and antidiabetic therapies. Despite this encouraging data, significant research gaps remain. Standardization of biomarkers, dose-response mapping, and long-term outcomes are urgently needed to move from proof-of-concept to clinical trials. Future directions include integrating mechanistic endpoints such as mitochondrial function and multi-omic profiling, exploring targeted delivery systems, and embedding implementation science to ensure real-world feasibility and equity. Collectively, the emerging evidence supports GSH-centered strategies as promising adjuncts for oxidative stress-driven chronic disease. Rigorous, well-designed trials are now required to define their definitive role in clinical care.

INTRODUCTION: Acne vulgaris (AV) is a chronic inflammatory dermatosis predominantly affecting adolescents and young adults. Oxidative and nitrosative stress, marked by elevated nitric oxide (NO) and interleukin (IL)-1α, contributes to AV pathogenesis. Glutathione, a key antioxidant, may attenuate oxidative and nitrosative stress and modulate inflammatory pathways. This study investigates the effectiveness of oral glutathione supplementation on serum NO and IL-1α concentrations, and clinical improvement in mild to moderate AV patients. METHODS: A randomized controlled trial was conducted involving 40 subjects diagnosed with mild to moderate AV. Participants were randomized to receive either 500 mg oral glutathione (n = 22) or placebo (n = 18) once daily for 4 weeks. Clinical severity of AV was assessed utilizing the Lehmann criteria. Serum levels of NO and IL-1α were measured at baseline and week 4. RESULTS: At week 4, reductions in serum NO and IL-1α concentrations were observed in the glutathione group; however, these changes did not reach statistical significance (p > 0.05). Clinical improvement occurred in seven subjects (31.8%) in the glutathione group, with a reduction from moderate to mild severity. No adverse reactions were reported. CONCLUSIONS: Oral glutathione supplementation demonstrated a non-significant trend toward reducing oxidative and nitrosative stress markers and improving mild to moderate AV. Further studies are recommended to validate these findings.

BACKGROUND: Melasma is a common acquired pigmentary disorder characterized by symmetrical hyperpigmented macules. However, combination therapy using tranexamic acid (TXA), vitamin C, and glutathione under nerve block remains inadequate. OBJECTIVE: To evaluate the efficacy and safety of intradermal injection of TXA, vitamin C, and glutathione under nerve block for melasma treatment. METHODS: A prospective, split-face trial was conducted on 20 patients with melasma during November 2023-July 2024. Lidocaine cream was applied to one side of the face, while infraorbital and zygomaticofacial nerve blocks were applied to the other. Intradermal injections of TXA, vitamin C, and glutathione were administered at weeks 2, 4, 6, and 8. Efficacy was assessed before treatment and three months post-treatment. RESULTS: VISIA analysis showed significant increases in UV spots and brown spots (P < 0.001), indicating improved skin condition. Modified Melasma Area and Severity Index (mMASI) scores decreased significantly from 6.99 ± 1.62 to 4.50 ± 1.27 (P < 0.001). Visual analog scale (VAS) pain scores were higher on to topical anesthesia side (4.35 ± 1.22) compared to the nerve block side (2.50 ± 0.83) (P < 0.001). No severe adverse events were reported. CONCLUSION: Intradermal injection of TXA, vitamin C, and glutathione under nerve block is an effective, safe, and low-pain treatment for melasma. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

BACKGROUND: Transfusion has a persistent low risk of transfusion-transmitted infection and transfusion-associated graft-versus-host disease that may be addressed using pathogen reduction. The Red Cell Pathogen Inactivation (ReCePI) trial tested whether amustaline/glutathione pathogen-reduced red cells are noninferior to conventional transfusions for support of acute surgical blood loss. METHODS: A phase 3, double-blinded, noninferiority trial randomized cardiac or thoracic-aorta surgery patients with increased risk of red cell transfusion to receive pathogen-reduced or conventional red cells during and for 7 days postsurgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI), which is defined as an increase from baseline of greater than or equal to 0.3 mg/dl serum creatinine within 48 h of surgery. Noninferiority was claimed if the upper bound 95% CI of the treatment difference was less than half (50%) of the observed conventional arm incidence. Adverse events and treatment-emergent red cell antibodies were assessed for 28 and 75 days, respectively. RESULTS: A total of 581 subjects were randomized, and 321 (55%) were transfused with study red cells. Transfused subjects in both arms had similar baseline demographics, medical histories, hemoglobin levels, and surgical procedures. Hemoglobin day 3 nadir levels (8.6 g/dl [7.8 to 9.2] in the pathogen-reduced arm; 8.4 g/dl [7.8 to 9.3] in the conventional arm; P = 0.52) were comparable. Incidence of AKI by 48 h was 46 of 157 (29.3%) in the pathogen-reduced arm and 45 of 161 (28.0%) in the conventional arm (treatment difference, 0.7%; 95% CI, -8.9 to 10.4%; noninferiority margin, 14.0%; P = 0.001 for noninferiority). AKI within 7 days by Kidney Disease Improving Global Outcomes staging criteria was not different (59 of 159 [37.1%] in the pathogen-reduced arm; 55 of 162 [34.0%] in the conventional arm; P = 0.53), but stage III was more common in the pathogen-reduced arm (pathogen-reduced arm, 15 of 159 [9.4%]; conventional arm, 7 of 162 [4.3%]; P = 0.075). Of 159 pathogen-reduced red cell recipients, 5 (3.1%) developed specific, low-titer antibodies without evidence of hemolysis. CONCLUSIONS: The incidence of AKI in recipients of pathogen-reduced red cells was noninferior to conventional red cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.

Glutathione (GSH) plays an important role in the antioxidant defense and body detoxification system. It is a tripeptide molecule consisting of glutamine, cysteine and glycine. It is mainly produced by the liver and is a powerful antioxidant that neutralizes free radicals and prevent cellules from damage. This review study was performed to explore the possible benefits and limitations of oral GSH supplementation in different conditions. The studies results indicated that GSH may considerably reduce oxidative stress. GSH's ability to eliminate free radicals and improve insulin sensitivity may contribute to its beneficial effect on diabetes management. Another result is that GSH could reduce oxidative damage, inflammation and improve the gastric mucosal repair Helicobacter-induced gastrointestinal diseases. Moreover, GSH supplementation exerts neuroprotective effects after a brief brain ischemic insult through the reduction of inflammation and oxidative stress. People with cystic fibrosis often have low GSH levels, which may lead to increased oxidative stress and lung inflammation. Oral GSH supplementation has been shown that could improve respiratory function, reduce lung damage and enhance antioxidant defense in cystic fibrosis patients. Also, GSH is gaining popularity as a skin-whitening ingredient because it can inhibit the production of melanin. Our results suggested that oral GSH supplementation may be beneficial for skin tone improvement and hyperpigmentation reduction. In conclusion, oral GSH supplementation can be useful for the treatment of neurodegenerative diseases, diabetic mellitus, stomach pathologies caused by Helicobacter, cystic fibrosis, transient cerebral ischemia attack, and skin-whitening conditions. Further research is needed to determine the best dosages, potential long-term benefits, and possible side effects of GSH supplementation in these conditions.

Acute radiation-induced intestinal injury (ARIII) is a common side effect of abdominopelvic radiotherapy, with severe diarrhea and hematochezia occurring in approximately 60-80% of patients. Radiation inevitably damages the adjacent intestine, generating substantial reactive oxygen species (ROS) that impair intestinal function. Nanozymes, which combine enzyme-like catalytic activities with the advantages of nanomaterials, have broad applications in biomedicine. Applying nanozymes to mitigate radiation-induced intestinal damage represents a promising therapeutic strategy. Here, we developed PtCuS nanoclusters (NCs) with favorable biocompatibility and demonstrated their efficacy in mitigating ARIII after irradiation. PtCuS NCs scavenge ROS via enzyme-mimetic activity and activate glutathione metabolism to mitigate radiation-induced cell death and inflammation. PtCuS NCs also modulate macrophage polarization, suppressing M1-like pro-inflammatory activation and promoting an M2-like reparative phenotype through both direct macrophage regulation and epithelial-protective effects. Furthermore, PtCuS NCs help restore gut microbiota composition and metabolic profiles after irradiation, providing a microbiota-associated component of intestinal protection. Importantly, PtCuS NCs alleviate ARIII without compromising the therapeutic efficacy of radiotherapy. These findings demonstrate that oral administration of PtCuS NCs may safely and effectively mitigate ARIII, highlighting their potential to improve the quality of life of patients undergoing abdominopelvic radiotherapy.