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N-acetylcysteine expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic acid-induced colitis in rats
Abstract and Figures
High free radical production, low antioxidant capacity and excessive inflammation are well known features in the pathogenesis of inflammatory bowel disease. N-acetylcysteine (NAC) is a powerful antioxidant and a scavenger of hydroxyl radicals. Recently, NAC has also been shown to have anti-inflammatory activities in tissues. Our study objective was to investigate the effects of NAC on tissue inflammatory activities using an ulcerative colitis model induced by acetic acid (AA) in rats. Wistar rats (n = 32) were divided into four groups. AA-induced colitis was performed in two of the groups while the other two groups were injected with saline intrarectally. One of the AA-induced colitis groups and one of the control groups were administered NAC (500 mg/kg/day) intrarectally, and the other control groups were given saline. After 4 days, colonic changes were evaluated biochemically by measuring proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6], myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels in tissue homogenates and by histopathological examination. AA caused colonic mucosal injury, whereas NAC administration suppressed these changes in the AA-induced colitis group (p < 0.001). AA-administration resulted in increased TNF-α, IL-1β, IL-6, MPO and MDA levels, and decreased GSH and SOD levels, whereas NAC reversed these effects (all p < 0.001). In conclusion, the present study proposes that intrarectal NAC therapy has a dual action as an effective anti-inflammatory and an antioxidant, and may be a promising therapeutic option for ulcerative colitis.
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... NAC was reported to repress ER-stress-mediated apoptosis during liver ischemia/reperfusion injury, which aligns with our results (Sun et al., 2014). Several reports demonstrated the pronounced antiinflammatory antioxidant effectiveness of NAC (Uraz et al., 2013;Tenório et al., 2021), which further supports our results. ER stress is known to be implicated in the pathology of many inflammatory disease models, including LPS-induced lung inflammation (Kim et al., 2013), high-fat diet-induced insulin resistance (Yuzefovych et al., 2013), or chronic graft-versus-host disease (Mukai et al., 2017). ...
Objectives
Hepatotoxicity is a severe outcome of methotrexate (MTX) therapy, limiting its clinical use and contributing to its related morbidity and mortality. This study investigated the hepatoprotective effects of nitazoxanide (NTZ), an antiprotozoal drug, against MTX-induced hepatotoxicity and whether endoplasmic reticulum (ER) stress-modulation underlies the expected beneficial effects of NTZ.
Methods
Thirty-six rats were allocated to six groups, one control group and five MTX groups, where induction of hepatotoxicity was achieved via injecting MTX (20 mg/kg). Groups were assigned as MTX-vehicle, NTZ-100, and NTZ-200 groups (at 100 and 200 mg/kg/day, gavage, respectively), N-acetyl cysteine (NAC) group (500 mg/kg), and 4-phenyl butyric acid (4-PBA) group (150 mg/kg, i.p). Liver function enzymes in serum, hepatic oxidative stress, proinflammatory cytokines, apoptosis, and ER-stress biomarkers were assessed. A histopathological examination was performed.
Results
Treatment with NTZ lessened the serum liver enzymes, reduced malondialdehyde (lipid peroxidation product), enhanced antioxidant capacity, attenuated proinflammatory cytokines, and suppressed apoptosis. The protective effect of NTZ was dose-dependent, and the findings observed with the high-dose NTZ were similar to those obtained with the ER-stress inhibitor (4-PBA).
Conclusion
NTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis.
... N-acetylcysteine is the precursor of cysteine and reduced glutathione. It is a compound containing sulfhydryl groups, which can interfere with the formation of free radicals and scavenge reactive oxygen radicals (Uraz, et al. 2013). During follicular development, granulosa cell proliferation and ovulation, the increase of metabolites reduces the activity of antioxidant enzymes, resulting in the rapid accumulation of ROS (Luo, et al. 2021), thus reducing the secretion of estrogen, promoting granulosa cell apoptosis and affecting the quality of oocytes (Tripathi, et al. 2013). ...
Granulosa cells are not only important supporting cells in follicular development, but also the main cells secreting steroids. The proliferation of GCs and steroid hormone synthesis play a key role in follicular development and atresia. In this experiment, GCs were isolated by follicular fluid aspiration, and identified by immunofluorescence technique. The effects of different concentrations of NAC (50, 100, 500, 1000 µmol/L) on sheep GCs with regards to the antioxidant levels, proliferation, apoptosis, and steroid hormone secretion were investigated. PI3K/AKT inhibitor LY294002 was used to explore the molecular mechanism of NAC on GCs proliferation and steroid hormone secretion in sheep. The results showed that in sheep GCs, all concentration of NAC group could promote the proliferation of GCs and inhibit their apoptosis. Among them, 100 µmol/L NAC had the most significant promote on the proliferation of sheep GCs for 48 h. The expression of CCND1 , CDK4 and Bcl-2 in all NAC concentration group was significantly increased, and the expression of Bax was significantly decreased. All concentrations of NAC significantly decreased reactive oxygen species (ROS) concentration and increased the expression of CAT and SOD1 . NAC significantly increased the expression of CYP19A1 , 3β-HSD and the secretion of estradiol (E 2 ) and progesterone (P 4 ) in GCs. In conclusion, NAC activates the PI3K/AKT signaling pathway to promote the proliferation of GCs, E 2 and P 4 secretion of sheep GCs in vitro.
Background: Psoriasis is a persistent, inflammatory skin disease with autoimmune characteristics. Beyond the obvious signs of skin lesions, it has negative systemic repercussions that impair the patient’s quality of life. This study aimed to determine the effectiveness of N-acetylcysteine (NAC) alone or in combination with Vitamin E in the treatment of mild to moderate active psoriasis vulgaris. Methods: This study was an open-label, prospective, randomized, controlled interventional clinical trial conducted at Cairo Hospital for Dermatology and Venereology (Al-Haud Al-Marsoud). In total, 45 patients with mild to moderate symptoms were randomly assigned to three groups, with fifteen patients each, as follows: the control group received the standard psoriatic treatment of topical steroids and salicylic acid; the acetylcysteine group received standard psoriatic treatment in addition to NAC 600 mg per day 30 min prior to breakfast for 8 weeks; and the acetylcysteine and Vitamin E group received standard psoriatic treatment in addition to NAC 600 mg per day, in a similar way of dosing like the previous group, and Vitamin E 1000 mg per day. All participants performed a comprehensive assessment including hematological parameters, the Psoriasis Area and Severity Index (PASI), the Dermatology Life Quality Index (DLQI), malondialdehyde (MDA), and interleukin-36 gamma (IL-36γ). Results: The treatment strategy involving the use of NAC alone and in combination with Vitamin E showed significant improvement in the assessed parameters compared to the control group receiving conventional therapy. The acetylcysteine group showed improvements of 41% in PASI and 49.4% in DLQI, a decrease of 34.3% in MDA, and a decrease of 31% in IL-36γ. Similarly, the acetylcysteine and Vitamin E group showed improvements of 52% in PASI and 42% in DLQI, a decrease of 37% in MDA, and a decrease of 35% in IL-36γ. There were no significant differences found between the N-acetylcysteine and N-acetylcysteine and Vitamin E groups. Moreover, significant positive correlations were found between MDA, IL-36γ, and PASI at baseline and after the third follow-up. Conclusions: This study found promising therapeutic benefits in the addition of NAC to the conventional therapy in psoriatic patients with mild to moderate symptoms, as it significantly improved psoriasis disease outcomes and improved the patient’s quality of life. However, the addition of Vitamin E to the NAC regimen did not show additional benefits.
Granulosa cells (GCs) are pivotal in the development of ovarian follicles, serving not only as supportive cells but also as the primary producers of steroid hormones. The proliferation of these cells and the synthesis of steroid hormones are crucial for follicular development and atresia. In our study, GCs were isolated using follicular fluid aspiration and subsequently identified through immunofluorescence. We investigated the impact of varying concentrations of N‐acetylcysteine (NAC) at 50, 100, 500, and 1000 μmol/L on sheep GCs, focusing on antioxidant levels, proliferation, apoptosis, and steroid hormone secretion. The phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 was used to explore the molecular mechanism of NAC on GCs proliferation and steroid hormone secretion in sheep. Our findings indicate that all concentrations of NAC tested promoted GC proliferation and suppressed apoptosis in sheep GCs. Notably, 100 μmol/L NAC exhibited the most pronounced effect on GC proliferation after 48 h. The expression levels of CCND1, CDK4, and Bcl‐2 were significantly elevated in all NAC concentration groups, whereas Bax expression was notably reduced. Furthermore, all NAC concentrations led to a significant reduction in reactive oxygen species (ROS) levels and an increase in the expression of CAT and SOD1. NAC also significantly enhanced the expression of CYP19A1 and 3β‐HSD, as well as the secretion of estradiol (E2) and progesterone (P4) by GCs. In summary, NAC activates the PI3K/AKT signalling pathway, thereby promoting the proliferation of GCs and the secretion of E2 and P4 by sheep GCs in vitro.
Recent studies show that inorganic arsenic (As) exerts a toxic effect on the intestinal epithelium, causing a significant increase in its permeability. This disruption of the epithelial barrier may favor the entry of contaminants or toxins into the systemic circulation, thus causing toxicity not only at the intestinal level but possibly also at the systemic level. The present study conducts an in vitro evaluation of the protective effect of various dietary supplements and plant extracts against the intestinal toxicity of inorganic As. Some of these compounds were found to exert a protective effect. A significant decrease was observed in intracellular reactive oxygen/nitrogen species (10-31%), as well as a lower secretion of the pro-inflammatory cytokine IL-8 (25-41%) in the intestinal monolayers treated with the supplements and extracts, compared with those exposed only to As(III). The most effective supplements (glutathione/cysteine/vitamin C and lipoic acid) also normalized the distribution of tight junction protein zonula occludens-1, with partial restoration of the paracellular permeability and cell regeneration capacity of the intestinal epithelial cells. The results obtained show that dietary supplements and plant extracts can reduce the intestinal barrier disruption caused by inorganic As, and this may have a positive impact at both local and systemic levels.
Background
Numerous natural products have been successfully developed for clinical use in the treatment of human diseases in almost every therapeutic area.
Objective
This work aimed to synthesize some new analogs of Carlina oxide by functionalizing the fifth position of the furan by different acyl groups using the Friedel-Crafts acylation approach. The synthetic analogs and carlina oxide were then assessed for their in-vitro anti-inflammatory activity and in-silico alpha-amylase inhibition effect.
Methods
The new analogs were synthesized at room temperature using different anhydrides with the presence of boron trifluoride diethyl etherate (BF3-Et2O) as an acid catalyst. A protein denaturation assay was performed to evaluate the anti-inflammatory activity, while the in-silico study was conducted using the Molecular Operating Environment (MOE) with different types of alphaamylase sources, such as human salivary pancreatic alpha-amylase and Aspergillus oryzae alphaamylase (PDB: 1Q4N, 5EMY, 7P4W respectively).
Results
A total of four analogs of carlina oxide were obtained in yields of 60-7% and then identified with 1H and 13C NMR analysis. Additionally, analog 1 exhibited a better anti-inflammatory effect with an IC50 of 0.280 mg/mL. However, the in-silico study showed that all the synthetic analogs have different interactions with human salivary alpha-amylase (1Q4N) and other interactions with 5EMY and 7P4W.
Conclusion
The new analogs of Carlina oxide have the potential to serve as an alternative agent for alpha-amylase inhibition, contributing to the reduction of postprandial hyperglycemia.
Many substances, even medicines with proven therapeutic benefits, can harm cells by metabolically activating them into extremely reactive substances. Paracetamol is one of the most widely used over-the-counter analgesics. This study examines the harmful effects of paracetamol on the lipid peroxidation process in testes homogenates as well as enzymatic and non-enzymatic antioxidant activities. Also, examine the effects on male hormones and sperm count. The study also assesses if N-acetylcysteine protects against testicular damage induced by paracetamol excess. Forty mature male albino rats were created. Group 1 as a control, Group 2 paracetamol (650 mg/kg), Group 3 NAC (150 mg/kg), and Group 4 both paracetamol and NAC. Samples of blood and testicles were taken after 15 days to measure sperm and testicular biochemistry. Testicular tissues had considerably higher amounts of MDA and H2O2. SOD, GSH, and CAT levels significantly decreased. FSH and LH rise. On the other hand, testosterone levels decrease following paracetamol exposure. The administration of NAC generated changes in testosterone levels, FSH, LH, and antioxidant enzymes. The sperm morphology showed an increase in abnormalities but a significant decrease in motility and count. NAC effectively lowers the toxicity of paracetamol to the testicles while restoring biomarkers associated with normal testicular function.
Background
Anxiety disorders, bipolar disorder, and depression are prevalent mental health issues that have a substantial impact on both individuals and the community. Many people continue to have symptoms and do not get the right kind of relief from their existing drugs, even after trying conventional therapy methods. Therefore, to enhance the current treatment modalities and patient results, new therapeutic alternatives are required. In recent years, there has been an increase in interest in N-acetylcysteine (NAC) because of its many biological benefits, including its ability to modulate glutamate levels and its antioxidant and anti-inflammatory properties. According to studies, NAC has encouraging antidepressant properties and may help treat bipolar disease by stabilizing mood and reducing the risk of relapses. Furthermore, through lowering oxidative stress and modifying neurotransmitter networks, NAC has been shown to lessen the symptoms of anxiety. The preclinical and clinical research examining the efficacy of NAC in depression, bipolar disorders, and anxiety are thoroughly analyzed in this review.
Methodology
Books were reviewed and medical and scientific literature found in MEDLINE and PubMed were analyzed for an assessment of NAC’s therapeutic potential in psychiatric illnesses such as anxiety, depression, and bipolar disorder.
Conclusion
NAC exhibits potential as a therapeutic agent for psychiatric problems such as anxiety, bipolar disorder, and depression. Performing a thorough clinical study will facilitate proper understanding its efficacy, safety and mechanisms of action.
This study was supported by grants from the Medical Research Council of Canada and the Canadian Foundation for Ileitis and Colitis. Dr. John L. Wallace is the recipient of a Medical Research Council of Canada Scholarship.
Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-α, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I-deficient mice after bleomycin administration. The exacerbation of bleomycin-induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin.
To investigate the anti-oxidant and anti-neutrophil recruitment effects of rectal d-alpha (d-alpha) tocopherol administration on mild and moderately active ulcerative colitis (UC).
Fifteen patients with mild and moderately active ulcerative colitis were enrolled in an open-label study of d-alpha tocopherol enema (8000 U/d) for 12 wk. All patients were receiving concomitant therapy with 5-aminosalicylic acid derivatives (5-ASA) and/or immunomodulator medications. Endoscopic evaluation was performed at baseline and after 4th and 12th weeks. Disease activity was measured with the Mayo disease activity index (DAI) and remission was defined as DAI of < or = 2 with no blood in stool. Clinical response was defined as a DAI reduction of > or = 2.
At the end of 12th week, the average DAI score significantly decreased compared to the beginning of the study (2.3 +/- 0.37 vs 8 +/- 0.48, P < 0.0001). One patient was withdrawn after 3 wk for being unavailable to follow-up. On the 4th week of therapy, 12 patients showed clinical response, 3 of whom (21.4%) achieving remission. After 12 wk, all 14 patients responded clinically to the therapy and remission was induced in 9 of them (64%). No patient reported adverse events or was hospitalized due to worsened disease activity.
This preliminary report suggests that rectal d-alpha tocopherol may represent a novel therapy for mild and moderately active UC. The observed results might be due to the anti-inflammatory and anti-oxidative properties of vitamin E.
We have developed a simple and reproducible rat model of chronic colonic inflammation by the intraluminal instillation of a solution containing a "barrier breaker" and a hapten. Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (5-30 mg) in 0.25 ml of 50% ethanol as the "barrier breaker" produced dose-dependent colonic ulceration and inflammation. At a dose of 30 mg, trinitrobenzenesulfonic acid/ethanol-induced ulceration and marked thickening of the bowel wall persisted for at least 8 wk. Histologically, the inflammatory response included mucosal and submucosal infiltration by polymorphonuclear leukocytes, macrophages, lymphocytes, connective tissue mast cells, and fibroblasts. Granulomas were observed in 57% of the rats killed 3 wk after induction of inflammation. Langhan's-type giant cells were also observed. Segmental ulceration and inflammation were common. The characteristics and relatively long duration of inflammation and ulceration induced in this model afford an opportunity to study the pathophysiology of colonic inflammatory disease in a specifically controlled fashion, and to evaluate new treatments potentially applicable to inflammatory bowel disease in humans.
Increased free radical production, decreased antioxidant capacity and excessive inflammation are well-known features in the pathogenesis of inflammatory bowel disease. Vitamin E is a powerful antioxidant and a scavenger of hydroxyl radicals, and it has been shown to have anti-inflammatory activities in tissues. We investigated the effects of vitamin E on inflammatory activities using an acetic acid (AA)-induced ulcerative colitis model in rats.
Wistar rats were divided into 4 groups. Acetic acid was given to 2 groups of animals to induce colitis while the other 2 groups received saline intrarectally. One AA-induced colitis group and 1 control group received vitamin E (30 U/kg/d) intraperitoneally and the pair groups received saline. After 4 days, we evaluated colonic changes biochemically by measuring proinflammatory cytokine levels in tissue homogenates and by histopathologic examination.
Acetic acid caused colonic mucosal injury, whereas vitamin E administration suppressed these changes in the AA-induced colitis group (p < 0.001). Administration of AA resulted in increased levels of tumour necrosis factor-α, interleukin-1β, interleukin-6, myeloperoxidase and malondialdehyde, and decreased levels of glutathione and superoxide dismutase; vitamin E reversed these effects (all p < 0.001).
Our study proposes that vitamin E is an effective anti-inflammatory and antioxidant and may be a promising therapeutic option for ulcerative colitis.
Innate immune cells play a role in modulating host immune response. Part of the macrophage inflammatory response is the release of an array of inflammatory cytokines, important molecules during the development of innate and adaptative immunity. Several antioxidant agents have been used in the control of the inflammatory response.
To evaluate the anti-inflammatory effect of N-acetylcysteine (NAC) on the expression and secretion of inflammatory cytokines and interleukin (IL)-10 in lipopolysaccharide (LPS)-activated THP-1 macrophages under mild oxidative conditions.
Macrophages were activated by LPS (0.1 and 1 μg/ml) for up to 24 h. The effect of 15 mM NAC was evaluated at 2, 4, 6 and 24 h. mRNA expression of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-8 and IL-10 was assessed by real time PCR. The expression of the corresponding cytokines plus IL-12p70 was analyzed using a bead array for flow cytometry.
NAC inhibits the inflammatory cytokines TNFα, IL-1β and IL-6 in LPS-activated macrophages under mild oxidative conditions. IL-10 mRNA and protein expression are strongly downregulated in NAC-treated cells, which may further modify the inflammatory cytokine profile.
NAC modulates immune functions during the inflammatory response.
Oxidative stress and inflammatory processes generate edema in burns. Treatment of consequent hypovolemia is a challenge. The aim of study was to assess if glutathione pro-drug N-acetylcysteine (NAC) can influence inflammation and fluid requirement. We also aimed to compare organ functions scores and vasoactive drug requirement. This prospective randomised study involved 28 patients with burn injury affecting more than 20% of body surface area. Fourteen patients were on standard therapy, whereas for other 14 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Leukocyte surface marker expressions were determined, multiple organ function scores, use of vasopressor agents and fluid requirements were recorded daily. Expression of CD11a (p < 0.05), CD18 (p < 0.05) and CD97 (p < 0.01) on the granulocytes were significantly lower in the NAC treated group, similarly to lymphocyte CD 49d (p < 0.05) and monocyte CD 49d (p < 0.01) and CD 97 (p < 0.05) expression. No significant difference was found in the fluid requirement between groups but patients the NAC group required less vasopressor and inotropic drugs from day 4. NAC treatment is associated with a less pronounced inflammation reflected in lower CD marker expression and vasopressor requirement.
Diffuse, topical application of dilute acetic acid to the serosal surface of rat colon, or standardized intraluminal (per rectum) instillation induced a reproducible, diffuse colitis in a dose-response manner. These lesions were reproduced with 100% reliability and were evaluated up to 60 days when healing occurred. Histopathological features of this chemically induced colitis were diffuse ulceration of the distal colon, occurrence of pseudopolyp-like structures, alterations in crypt depth and mucus secretion, and a transmural, nonspecific inflammatory response.