NAC

 

• NAC improved liver function in patients with NAFLD (34% reduction in ALT, 31% reduction in AST after 3 months @ 600mg x 2)

• GlyNAC supplemention (glycine+NAC) extends mouse lifespan by 24% when started at 65 weeks of age. 

• In patients with acute liver failure, NAC significantly improves overall survival, post-transplant survival and transplant-free survival .

• GlyNAC improved: eGFR, Glucose, Insulin, Glucose, HOMA-IR, IL6, TNF-alpha, HS-CRP, exercise capacity, gait speed, 6 min walk, grip strength in older patients with or w/o HIV.

• Inhibits thrombosis in JAK2V617F mice (a murine model of myeloproliferative neoplasm). Extended survival of the JAK2V617F mice. 

• Inhibited platelet–monocyte conjugation in patients with T2D (a known risk factor for thrombosis).

• PV symptom burden was significantly lower among those taking NAC (2.4 versus 3.4; p = 0.02).

• PV Mice study: Treatment with NAC substantially restored blood parameters and reduced damages to DNA. Furthermore, NAC induced a marked decrease in splenomegaly with reduction in the frequency of the Jak2V617F-positive hematopoietic progenitors in BM and spleen. 

• Overproduction of ROS is a mediator of JAK2V617F-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of JAK2V617F MPNs.

• Supplementation reduced breast cancer invasiveness significantly in a human clinical trial with 12 participants. Significantly inhibited tumor stroma.

• [NEUTRAL] 2-year supplementation of NAC resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer.

• Improved serum testosterone in males (387 → 437). Semen parameters significantly improved with selenium and NAC treatment. Administering selenium plus NAC resulted in additive beneficial effects.

• Supplementing with NAC (600 mg/d for 4 wk) decreased GGT by 25%.

GlyNAC Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage, 2022

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation. View Full-Text

N-Acetylcysteine Improves Liver Function in Patients with Non-Alcoholic Fatty Liver Disease, 2010

Background and Aims

Non-alcoholic fatty liver change is a common disease of the liver in which oxidative stress plays a basic role. Studies are largely focused on protecting the liver by means of anti-oxidative material. The aim of this study is to evaluate the role of N- acetylcysteine in the process of liver injury.

Methods

Thirty patients with non-alcoholic fatty liver steatosis were randomly selected to receive either N-acetylcysteine or vitamin C. Received either NAC (600 mg per 12 hours) or vitamin C (1000 mg per 12 hours). Liver function tests (alanine aminotransfrase, aspartate aminotransfrase and alkaline phosphatase) were measured as well as the grade of steatosis, the pattern of its echogenicity, the span of the liver and the spleen and the portal vein diameter before the intervention. Patients were followed up using the same method of evaluation repeated in the first, second and third months.

Results

The mean age (SD) was 40.1(12.4) in patients receiving NAC and 46(10.4) years in patients receiving vitamin C (P = 0.137). NAC resulted in a significant decrease of serum alanine aminotransfrase after three months, compared to vitamin C. This effect was independent of the grade of steatosis in the initial diagnosis. NAC was able to significantly decrease the span of the spleen.

Conclusions

N-acetylcysteine can improve liver function in patients with non-alcoholic fatty liver disease. Better results may be achievable in a longer follow up.

Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review, 2022

Background

The American Association for the Study of Liver Diseases recommends that N-acetylcysteine (NAC) may be beneficial in non-acetaminophen-related drug-induced liver injury. A subsequent review and analysis reported the current evidence to be inconclusive. Herein, we present an updated review and meta-analysis.

Methods

We evaluated prospective, retrospective and randomized controlled trials that compared outcomes in patients of all ages with acute liver failure (defined as abnormal liver enzymes along with elevated international normalized ratio >1.5, with or without hepatic encephalopathy) receiving NAC with the outcomes in a control group. The primary outcome was to compare the overall survival in the 2 groups. Secondary outcomes included difference in length of hospital stay, transplant-free survival, and post-transplant survival.

Results

Seven studies (N=883) that met the inclusion criteria were included in this analysis. The mean age of patients in the NAC group was 21.22 years compared with 23.62 years in the control group. The odds of overall survival were significantly higher in the NAC group than in controls (odds ratio [OR] 1.77, 95% confidence interval [CI] 1.3-2.41). Post-transplant survival (OR 2.44, 95%CI 1.11-5.37) and transplant-free survival were also better in the NAC group than in the control group (OR 2.85, 95%CI 2.11-3.85). Patients in the control group had statistically significant odds of a longer inpatient stay (mean difference 7.79, 95%CI 6.93-8.66).

Conclusion

In patients with non-acetaminophen-related acute liver failure, NAC significantly improves overall survival, post-transplant survival and transplant-free survival while decreasing the overall length of hospital stay.

Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial, 2021

Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition.

Methods

A 36-week open-label clinical trial was conducted in eight Old Adults (OAs) and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition.

Results

GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.

Conclusions

GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.

Precaution against taking high doses of NAC: link.

Improvements: IL6, TNF-alpha, HS-CRP, Glucose, Insulin. Trigs, eGFR

Fat mass (but not weight), waist circumference, gait speed, grip strength.

Supplementing Glycine and N-acetylcysteine (GlyNAC) in Aging HIV Patients Improves Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Endothelial Dysfunction, Insulin Resistance, Genotoxicity, Strength, and Cognition: Results of an Open-Label Clinical Trial, 2020

Background: Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC). Methods: We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition. Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC. Conclusions: This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, and warrants additional investigation.

Improvements: eGFR, Glucose, Insulin, Glucose, HOMA-IR, IL6, TNF-alpha, HS-CRP, Gait speed, 6 min walk, grip strength

Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors, 2018

Metabolic, inflammatory, and functional changes occur in cardiovascular aging which may stem from oxidative stress and be remediable with antioxidants. Glutathione, an intracellular antioxidant, declines with aging, and supplementation with glutathione precursors, N-acetyl cysteine (NAC) and glycine (Gly), increases tissue glutathione. Thirty-month old mice were fed diets supplemented with NAC or NAC+Gly and, after 7 weeks, cardiac function and molecular studies were performed. The NAC+Gly supplementation improved diastolic function, increasing peak early filling velocity, and reducing relaxation time, left atrial volume, and left ventricle end diastolic pressure. By contrast, cardiac function did not improve with NAC alone. Both diet supplementations decreased cardiac levels of inflammatory mediators; only NAC+Gly reduced leukocyte infiltration. Several mitochondrial genes reduced with aging were upregulated in hearts by NAC+Gly diet supplementation. These Krebs cycle and oxidative phosphorylation enzymes, suggesting improved mitochondrial function, and permeabilized cardiac fibers from NAC+Gly-fed mice produced ATP from carbohydrate and fatty acid sources, whereas fibers from control old mice were less able to utilize fatty acids. Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people.

May improve fertility in both men and women

Many male infertility issues increase when antioxidant levels are insufficient to address free radical formation in the reproductive system. The oxidative stress can cause cell death and reduced fertility (28).

In some cases, NAC has been shown to improve male fertility.

One condition that contributes to male infertility is varicocele — when veins inside the scrotum become enlarged as a result of free radical damage. Surgery is the primary treatment.

In one study, 35 men with varicocele received 600 mg of NAC per day for 3 months after surgery. The combination of surgery and NAC supplementation improved semen integrity and partner pregnancy rate by 22% compared with the control group (29).

An older study in 468 men with infertility found that supplementing with 600 mg of NAC and 200 mcg of selenium for 26 weeks improved semen quality (30).

Life Extension by Diet Restriction and N-Acetyl-l-Cysteine in Genetically Heterogeneous Mice (2010)

We used a heterogeneous stock of mice—UM-HET3, the first generation offspring of CByB6F1/J and C3D2F1/J parents—to test effects of six antiaging treatments on life span. In the first report of diet restriction in a structured, segregating heterogeneous population, we observed essentially the same increases in mean and maximum life span as found in CByB6F1/J hybrid positive controls. We also report results of treatment with N-acetyl-l-cysteine started at 7 months, and aspirin, nitroflurbiprofen, 4-hydroxy phenyl N-tert-butyl nitrone, and nordihydroguaiaretic acid, all started at 16–18 months. Only male UM-HET3 mice receiving N-acetyl-l-cysteine had significantly increased life span, and this may have been due to treatment-related inadvertent diet restriction. The other agents had no significant effects on life span. The use of UM-HET3 mice helps assure that these results are not the result of unresponsiveness of a single genotype but that they more broadly represent laboratory mice.

N-Acetyl-l-Cysteine

NAC has attracted interest among gerontologists as a potential “antiaging” treatment because of its antitumor, antioxidant, and other antiaging characteristics. In HET3 females, we detected no benefits of NAC treatment at either a low or a high treatment dose. In HET3 males, we observed increases in overall life span at both low and high doses, and an increase in maximum life span at the higher dose. In both males and females, however, both doses of NAC caused a sudden drop in body weight, followed by a further slow decline (Figure 4). At 900 days of age, body weights in NAC-treated mice were the same in males and only 2 g heavier in females than weights of age-matched mice treated with DR. Thus, beneficial effects of NAC on life span may have resulted simply from self-imposed DR. It would be interesting to perform a complementation test, in which diet-restricted mice are given NAC, to determine whether effects on life span are additive or complementary, and to determine if any antiaging benefits correlate with antitumor effects or can be predicted by increased glutathione or decreased insulin-like growth factor-1 levels.

A role for reactive oxygen species in JAK2V617F myeloproliferative neoplasm progression (2013)

Although other mutations may predate the acquisition of the JAK2V617F mutation, the latter is sufficient to drive the disease phenotype observed in BCR-ABL-negative myeloproliferative neoplasms (MPNs). One of the consequences of JAK2V617F is genetic instability that could explain JAK2V617F-mediated MPN progression and heterogeneity. Here, we show that JAK2V617F induces the accumulation of reactive oxygen species (ROS) in the hematopoietic stem cell compartment of a knock-in (KI) mouse model and in patients with JAK2V617F MPNs. JAK2V617F-dependent ROS elevation was partly mediated by an AKT-induced decrease in catalase expression and was accompanied by an increased number of 8-oxo-guanines and DNA double-strand breaks (DSBs). Moreover, there was evidence for a mitotic recombination event in mice resulting in loss of heterozygosity of Jak2V617F. Mice engrafted with 30% of Jak2V617F KI bone marrow (BM) cells developed a polycythemia vera-like disorder. Treatment with the anti-oxidant N-acetylcysteine (NAC) substantially restored blood parameters and reduced damages to DNA. Furthermore, NAC induced a marked decrease in splenomegaly with reduction in the frequency of the Jak2V617F-positive hematopoietic progenitors in BM and spleen. Altogether, overproduction of ROS is a mediator of JAK2V617F-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of JAK2V617F MPNs.

Diet Choices and Supplement Use May Affect MPN Symptom Burden (2017)

PV symptom burden was significantly lower among those taking amino acid supplements (2.8 versus 3.4; p = 0.02) and N-acetylcysteine (2.4 versus 3.4; p = 0.02).

NAC inhibits thrombosis in a murine model of myeloproliferative neoplasm, 2020

Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN.

NAC has the potential to inhibit thrombosis caused by the JAK2V617F mutation, 2020

Abstract

Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN.

N-Acetylcysteine inhibits platelet–monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial, 2012

Aims/hypothesis

Determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet–monocyte conjugation in blood from patients with type 2 diabetes.

Methods

Patients (n = 14; age range 43–79 years, HbA1c = 6.9 ± 0.9% [52.3 ± 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. 

Results

Oral NAC reduced platelet–monocyte conjugation (from 53.1 ± 4.5% to 42.5 ± 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH.

Platelet–monocyte conjugation is gaining recognition as an effective marker for cardiovascular risk [29–32]. Elevated platelet–monocyte conjugation is indicative of an increased level of circulating platelet activation, which might predispose to thrombus. 

Conclusions/interpretation

The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet–monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes.

The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms, 2015

Reactive oxygen species (ROS) have been implicated in a wide variety of disorders ranging between traumatic, infectious, inflammatory, and malignant diseases. ROS are involved in inflammation-induced oxidative damage to cellular components including regulatory proteins and DNA. Furthermore, ROS have a major role in carcinogenesis and disease progression in the myeloproliferative neoplasms (MPNs), where the malignant clone itself produces excess of ROS thereby creating a vicious self-perpetuating circle in which ROS activate proinflammatory pathways (NF-κB) which in turn create more ROS. Targeting ROS may be a therapeutic option, which could possibly prevent genomic instability and ultimately myelofibrotic and leukemic transformation. In regard to the potent efficacy of the ROS-scavenger N-acetyl-cysteine (NAC) in decreasing ROS levels, it is intriguing to consider if NAC treatment might benefit patients with MPN. The encouraging results from studies in cystic fibrosis, systemic lupus erythematosus, and chronic obstructive pulmonary disease warrant such studies. In addition, the antioxidative potential of the widely used agents, interferon-alpha2, statins, and JAK inhibitors, should be investigated as well. A combinatorial approach using old agents with anticancer properties together with novel JAK1/2 inhibitors may open a new era for patients with MPNs, the outlook not only being “minimal residual disease” and potential cure but also a marked improvement in inflammation-mediated comorbidities.

N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps, 1999

This investigation is part of an effort to develop chemoprevention for carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine (NAC). We used as a predictive biomarker, the proliferative index (PI), in a short-term human study. Patients with previous adenomatous colonic polyps are a cohort with increased risk for colon cancer and an increased PI of colonic crypts. They were randomly assigned to an experimental group given 800 mg/day of NAC for 12 weeks or a placebo group. Using proliferative cell nuclear antigen immunostaining, the PI of colonic crypts was measured prior to and after the treatments. The PI of the NAC group was decreased significantly (P < 0.02) while the placebo group showed no difference (P > 0.45). Since this decrease in PI may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted.

Colon cancer prevention

A preliminary double-blind, placebo-controlled study of NAC enrolled 62 individuals, each of whom had had a polyp removed from the colon.40 The abnormal growth of polyps is closely associated with the development of colon cancer. In this study, the potential anticancer benefits of NAC treatment were evaluated by taking a biopsy of the rectum. Individuals taking NAC at 800 mg daily for 12 weeks showed more normal cells in the biopsied tissue as compared to those in the placebo group.

EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups, 2000

Background: Preclinical evidence suggests that retinoids and antioxidants may prevent or delay the occurrence of cancer in the upper or lower airways, but such effects have not been reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and N-acetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking.

Methods: From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) were randomly assigned to receive 1) retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for a 2(nd) year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both compounds, or 4) no intervegdf

ntion. All statistical tests were two-sided.

Results: Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to smoke after cancer diagnosis). After a median follow-up of 49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or event-free survival between patients who received retinyl palmitate and patients who did not. Similarly, no difference was seen in overall survival or event-free survival between patients who received N-acetylcysteine and patients who did not. There was a lower incidence of second primary tumors in the no intervention arm, but the difference was not statistically significant.

Conclusion: A 2-year supplementation of retinyl palmitate and/or N-acetylcysteine resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer, most of whom were previous or current smokers.

Decongestant revealed as 'highly effective' in starving cancer cells, 2017

Cancer researchers seeking non-toxic alternatives to harmful chemotherapy are reporting a highly significant result for a humble cold remedy.

N-Acetyl cysteine -- or NAC -- is routinely used as a dietary supplement and as a decongestant given to children to ward off a cold.

Now, clinical trials in the US indicate the cheap, over-the-counter drug, is a first rate inhibitor of the tumour stroma, a cell compartment which is fundamental to the spread of cancer.

The results, published in Seminars in Oncology, confirm a long-held theory that cancer cells are being sustained and strengthened by the presence of MCT4, a protein which 'brings them' energy, in the form of lactate, from neighbouring cells.

Patients taking high dosages of NAC saw their levels of the 'transporter' protein fall by more than 80%, drastically reducing the ability of the cancer cells to feed off neighbouring cells.

Professor Federica Sotgia, of the Biomedical Research Centre at the University of Salford, UK, explained: "In cell cultures in the laboratory, we had seen a near complete reduction in MCT4, but to achieve such a substantial result in breast cancer patients is extremely exciting indeed."

The team, which includes Professor Michael Lisanti, of the University of Salford and US-based Ubaldo Martinez-Outschoorn, MD, conducted a 'window trial' on 12 patients awaiting surgery for breast cancer at The Sidney Kimmel Cancer Center (Thomas Jefferson University), in Philadelphia.

Patients were given maximum daily dosages of the over-the-counter drug for three weeks between diagnosis and surgery. Tumour tissue biopsies were then taken before and during surgery and key biomarkers, including MCT4 and K167, were measured post-surgery.

K167 levels fell by 25% and MCT4 levels were reduced by approximately 80%.

"High levels of stromal MCT4 are extremely worrying, as they are linked to aggressive cancer behaviour and poor overall survival, so this is very encouraging result," explained Professor Lisanti.

"Our idea was to repurpose an inexpensive FDA-approved drug, to examine if its antioxidant properties could target the feeding behaviour of cancer cells. To be able to inhibit MCT4 protein expression, in a non-toxic way, is huge step forward."

Researchers suggest that NAC could be used to halt cancer cell growth, 2017

Prof. Sotgia and team note that previous research has identified high levels of oxidative stress in the stromal cells of tumors, particularly breast cancer tumors. Stromal cells are cells that comprise connective tissue.

The researchers explain that when the stromal cells of tumors are exposed to oxidative stress, they release lactate and other “nutrients” that the cancer cells need to thrive.

With this in mind, the team hypothesized that the antioxidant properties of NAC might help to “starve” cancer cells of these nutrients.

‘Encouraging results’

To test their theory, the researchers conducted a trial on 12 women who had recently received a diagnosis of stage 0 or stage 1 breast cancer, and who were awaiting surgery for the disease.

For 3 weeks between their breast cancer diagnosis and surgery, each woman received NAC. The medication was administered intravenously at a dose of 150 milligrams per kilogram once weekly. On days when the subjects did not receive NAC intravenously, they received a twice-daily oral dose of 600 milligrams.

Biopsies of each woman’s breast cancer tumor were taken both prior to and during surgery, and the researchers analyzed them for levels of three biomarkers of cancer aggressiveness: MCT4, CAV1, and Ki67.

The study revealed that levels of Ki67 in the tumors had reduced by 25 percent, while levels of MCT4 were reduced by a whopping 80 percent.

These findings indicate that treatment with NAC could be an inexpensive, non-toxic way to stop cancer cell growth and division.

“High levels of stromal MCT4 are extremely worrying,” notes study co-author Prof. Michael Lisanti, also of the School of Environment and Life Sciences at the University of Salford, “as they are linked to aggressive cancer behavior and poor overall survival, so this is very encouraging result.”

“Our idea was to repurpose an inexpensive FDA-approved drug, to examine if its antioxidant properties could target the feeding behavior of cancer cells. To be able to inhibit MCT4 protein expression, in a non-toxic way, is huge step forward.”

Combining NAC with Interferon Alpha

• N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells, 2012

• N-Acetyl Cysteine Enhances the Response to Interferon-α in Chronic Hepatitis C: A Pilot Study, 1993

• Combination therapy with interferon-α plus N-acetyl cysteine for chronic hepatitis C: A placebo controlled double-blind multicentre study, 2000

Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status, 2015

We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers.. We evaluated the effect of 4 wk of oral NAC (1.8 g/d).

NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008).

(Dark = NAC group).

Glutathione Restoration Improves Hallmarks Of Aging in Older Adults (link)

7g Glycine/day + 9.3g NAC/day for a 70kg person

“most NAC trials use 2-3 grams/day; 600 mg QID (four times daily) is popular. In cardiovascular settings, high-dose NAC (15 grams/day) has been used, but only for a couple days, such as post-infarct. It would be risky or reckless to use such high doses for an extended period. A case has been reported of hemolysis and acute renal failure in a woman accidentally given a massive dose of NAC: 52 grams, IV, in one hour, followed by 17 grams over the next four hours (PMID 21970774). That's an extreme case, but still.” (link)

Glutathione!, 2014

GGT as Measure of Glutathione Need

GGT (gamma-glutamyl transferase) is upregulated in proportion to the need for glutathione such as for the detoxification of POPs.19 It provides the rate-limiting cysteine through a catabolic “salvage pathway.” Increases in GGT correlate with many diseases: metabolic syndrome, both fatal and nonfatal coronary heart disease (CHD) events, atherosclerosis, fatty liver, diabetes, cancer, hypertension, and carotid intima-media thickness.20–22 Of particular note, these are elevations of GGT within the supposedly “normal” range. For example, men with a GGT of 40 to 50 have a 20-fold increased risk of diabetes.23 Research also shows a GGT 30 to 40—well within the normal range—is associated with a doubling of the risk of all-cause mortality.24 2

Ways to Increase Intracellular Glutathione

Finally, we can provide specific nutrients to promote glutathione production. As noted above, cysteine availability is the rate-limiting step in the de novo production of glutathione. While oral cysteine does not make it through the digestive track, supplemental cysteine in the form of whey or N-acetylcysteine (NAC) is effective at raising levels. While there is substantial variation, 1000 mg/d of NAC will substantially increase glutathione in virtually all patients.30 For the rare patient who reacts to NAC, SAMe can be used.31 Do not use methionine as it will increase homocysteine. Interestingly, supplementing with NAC (600 mg/d for 4 wk) decreases GGT 25%, suggesting that increasing de novo synthesis decreases the need for GGT recycling.32

For those looking for a nonsupplemental solution, 500 mL of alcohol-free beer per day raises RBC glutathione 29%!33 There are many other examples of foods that increase glutathione. For example, 83 g/d of almonds increases glutathione in smokers by 16% and decreases their DNA damage by 29%.34

Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men (link)

Hormonal analysis Before NAC (n = 50) After NAC (n = 50) P-Value

FSH (mIU/mL)                 4.14 ± 0.17               3.67 ± 0.19             0.01

LH (mIU/mL)                 4.20 ± .060               4.07 ± .054             0.04

Testosterone (ng/dL)     387 ± 1.5                 437 ± 1.7             0.01  (+50 pts)

These results align with a previous study that reported improved serum testosterone after supplementation with NAC [22].

Abstract

Background

Infertile men have higher levels of semen reactive oxygen species (ROS) than fertile men. High levels of semen ROS can cause sperm dysfunction, sperm DNA damage and reduced male reproductive potential. This study investigated the effects of supplementation with N-acetyl-cysteine (NAC) on the sperm quality, chromatin integrity and levels of oxidative stress in infertile men.

Methods

The study was carried out in the unit of ACECR Infertility Research Center, Qom, Iran. The patients consisted of 50 infertile men with asthenoteratozoospermia who received NAC (600 mg/d) orally for 3 months, after which they were compared with pre-treatment status. Semen was analyzed according to WHO (2010), followed by the assessment of protamine content [chromomycin A3 (CMA3)] and DNA integrity [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)]. Oxidative stress markers, i.e. total antioxidant capacity (TAC) and malondialdehyde (MDA), as well as hormonal profile (LH, FSH, Testosterone and Prolactin) were determined by ELISA kit.

Results

After NAC treatment, patients’ sperm count and motility increased significantly whereas abnormal morphology, DNA fragmentation and protamine deficiency showed significant decreases compared to pre-treatment levels (P < 0.05). Hormonal profile improvement was associated with lowered FSH and LH levels and increased amount of testosterone (P < 0.05). TAC significantly increased and MDA decreased with an inverse significant correlation between TAC and MDA (P < 0.05).

Conclusion

NAC oral supplementation may improve sperm parameters and oxidative/antioxidant status in infertile males.

Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study 

Purpose: We explored the efficacy of selenium and/or or N-acetyl-cysteine for improving semen parameters in infertile men, and the associations among semen quality and the concentrations of selenium and N-acetyl-cysteine in seminal plasma.

Materials and methods: The study included 468 infertile men with idiopathic oligo-asthenoteratospermia who were randomized to receive 200 microg selenium orally daily (selenium group of 116), 600 mg N-acetyl-cysteine orally daily (N-acetyl-cysteine group of 118), 200 microg selenium plus 600 mg N-acetyl-cysteine orally daily (selenium plus N-acetyl-cysteine group of 116) or similar regimen of placebo (control group of 118) for 26 weeks, followed by a 30-week treatment-free period. These patients provided blood samples for the measurement of serum testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, inhibin B, selenium and N-acetyl-cysteine. Semen samples were also obtained for routine semen analysis, and the measurement of seminal plasma selenium and N-acetyl-cysteine.

Results: In response to selenium and N-acetyl-cysteine treatment serum follicle-stimulating hormone decreased but serum testosterone and inhibin B increased. All semen parameters significantly improved with selenium and N-acetyl-cysteine treatment. Administering selenium plus N-acetyl-cysteine resulted in additive beneficial effects. A significant positive correlation existed between the seminal plasma concentrations of selenium and N-acetyl-cysteine, and semen parameters. A strong correlation was observed between the sum of the selenium and N-acetyl-cysteine concentrations, and mean sperm concentration (r = 0.67, p = 0.01), sperm motility (r = 0.64, p = 0.01) and percent normal morphology (r = 0.66, p = 0.01).

Conclusions: These results indicate that supplemental selenium and N-acetyl-cysteine improve semen quality. We advocate their use for male infertility treatment.