Labetalol Ameliorates Experimental Colitis in Rat Possibly Through its Effect on Proinflammatory Mediators and Oxidative Stress.

BACKGROUND: Members of beta blockers drugs possess significant antioxidant activities. The current research is to assess the effect of the labetalol on acetic acid (AA-induced) colitis in rat model. METHODS: Forty adult Wistar rats were separated into 4 groups, including the negative control group, AA group, AA + sulfasalazine (100 mg/kg/day) group, and AA + labetalol (300 mg/kg/day) group. Colitis was induced in rats by the interrectal installation of 2 mL of 4% (v/v) AA. Sulfasalazine and labetalol were administered orally for 7 days after 2 hours of induction. The following parameters were measured: disease activity index (DAI), histopa-thological changes and colon tissue homogenate concentrations of proinflammatory mediators IL-1ß, adhesion molecules ICAM-1, and oxidative stress marker myeloperoxidase (MPO). RESULTS: The treatment with labetalol significantly reduced DAI and histopathological changes induced by AA. Also, labetalol markedly decreased the concentrations of IL-1ß, ICAM-1, and MPO in colonic tissue that were increased by AA. The effects of labetalol were significantly lower than that produced by sulfasalazine as standard drug. CONCLUSIONS: Labetalol exerts ameliorative effects on disease activity and histopathological features of AA-induced colitis in rats possibly through antioxidant effects and inhibition of inflammatory mediators.

Protective effects of topiramate on acetic acid-induced colitis in rats through the inhibition of oxidative stress.

Ulcerative colitis is an intestinal inflammatory condition characterized by a rise in inflammatory mediator production and oxidative stress. Topiramate is an anticonvulsant agent with effectiveness on a wide range of seizures, which is anti-oxidative. This study aims to examine the protective effects of topiramate on acetic acid-induced ulcerative colitis in rats. Rats were randomly divided into four groups as follows: control, acetic acid, acetic acid + topiramate, and acetic acid + dexamethasone groups. Topiramate (100 mg/kg/day) or dexamethasone (2 mg/kg/day) was administered for six consecutive days, and ulcerative colitis was induced on the first day of the study by transrectal administration of 4% acetic acid. Four hours after the last dose of treatments, animals of each group were sacrificed, and colon tissues were removed for further macroscopic, histopathologic, and biochemical analyses. Treatment with topiramate markedly decreased colonic lesions and macroscopic scores as well as the improvement of histopathologic changes. Topiramate also effectively decreased the levels of malondialdehyde and upregulated the activity of anti-oxidative enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Our results reveal that the administration of topiramate ameliorates acetic acid-induced colitis in rats via anti-oxidative properties, and further studies may introduce it as an effective therapeutic candidate to decrease ulcerative colitis severity.

Evaluation of anti-inflammatory activity of kaurenol: Experimental evaluation and mechanistic insights.

BACKGROUND: Kaurenol, a diterpene alcohol found in Copaifera langsdorffii Desf. (known as "copaiba"), is historically used in traditional medicine for inflammatory conditions. OBJECTIVES: This study aims to comprehensively assess the potential anti-inflammatory and antinociceptive properties of kaurenol. METHODS: To this end, the following experiments were conducted to evaluated toxicity: locomotor performance and acute toxicity; nociception: acetic acid-induced writhing and formalin-induced antinociception; and anti-inflammatory activity: carrageenan and dextran-induced paw edema at 10, 20, and 40 mg/kg, and measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in macrophages at 1, 3, and 9 µg/ml. RESULTS: Kaurenol did not show significant locomotor changes, acute toxicity, and central analgesic activity in the first phase of formalin test at dosages tested. Kaurenol showed 53%, 64%, 64%, and 58% of inhibition in the acetic acid-induced writhing, second phase of formalin test, carrageenan and dextran-induced paw edema, respectively. CONCLUSION: The anti-inflammatory activity was associated with the regulation of NO release and probably with the regulation of mediators, such as serotonin and prostaglandin in vascular permeability, as well as by being associated with the regulation of IL-6 and IL-10. Kaurenol display anti-inflammatory activity but has no analgesic activity.

Ameliorative effects of androstenediol against acetic acid-induced colitis in male wistar rats via inhibiting TLR4-mediated PI3K/Akt and NF-κB pathways through estrogen receptor ß activation.

5-androstenediol (ADIOL) functions as a selective estrogen receptor ß (ERß) ligand with a protective effect against many diseases. So, we conducted a novel insight into its role in acetic acid (AA)-induced colitis and investigated its effect on TLR4-Mediated PI3K/Akt and NF-κB Pathways and the potential role of ERß as contributing mechanisms. METHODS: Rats were randomized into 5 Groups; Control, Colitis, Colitis + mesalazine (MLZ), Colitis + ADIOL, and Colitis + ADIOL + PHTPP (ER-ß antagonist). The colitis was induced through a rectal enema of acetic acid (AA) on the 8th day. At the end of treatment, colons were collected for macroscopic assessment. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor kappa b (NF-κB), toll-like receptor (TLR4), and phosphorylated Protein kinase B (pAKT) were measured. Besides, Gene expression of interleukin-1beta (IL-1ß), metalloproteases 9 (Mmp9), inositol 3 phosphate kinase (PI3K), Neutrophil gelatinase-associated lipocalin (NGAL), ERß and NLRP6 were assessed. Histopathological and immunohistochemical studies were also investigated. RESULTS: Compared to the untreated AA group, the disease activity index (DAI) and macroscopic assessment indicators significantly decreased with ADIOL injections. Indeed, ADIOL significantly decreased colonic tissue levels of MDA, TLR4, pAKT, and NF-κB immunostainig while increased SOD activity and ß catenin immunostainig. ADIOL mitigated the high genetic expressions of IL1ß, NGAL, MMP9, and PI3K while increased ERß and NLRP6 gene expression. Also, the pathological changes detected in AA groups were markedly ameliorated with ADIOL. The specific ERß antagonist, PHTPP, largely diminished these protective effects of ADIOL. CONCLUSION: ADIOL could be beneficial against AA-induced colitis mostly through activating ERß.

Juglone Mediates Inflammatory Bowel Disease Through Inhibition of TLR-4/NF KappaB Pathway in Acetic Acid-induced Colitis in Rats.

BACKGROUND: Juglone is a phenolic bioactive compound with antimicrobial, antitumour, antioxidant, and anti-inflammatory characteristics. Given its anti-inflammatory and antioxidant effects, it was selected for evaluation in the inflammatory bowel diseases (IBD) model. OBJECTIVE: The current study was performed to evaluate the therapeutic impacts of the juglone in acetic acid-induced colitis in male Wistar rats. METHODS: Juglone was extracted from Pterocarya fraxinifolia via maceration method. Colitis was induced in 36 male Wistar rats (n = 6), except in the sham group, 1 ml of acetic acid 4% was administered intrarectally. Twenty-four hours after induction of colitis, in 3 groups, juglone was administered orally (gavage) at 3 doses of 50, 100, and 150 mg/kg for 2 successive days (once a day). Other groups included the control group (only treated with acetic acid), sham group (normal saline), and standard group (Dexamethasone). To evaluate the inflammation sites, macroscopic and microscopic markers were assessed. The mRNA expression of interleukin (IL)-1ß, and tumor necrosis factor-alpha (TNF)-α were assessed by real-time PCR, while myeloperoxidase (MPO) was measured spectrophotometrically. ELISA assay kits were used to determine the colonic levels of SOD, ROS, NF-κB, and TLR-4. RESULTS: Macroscopic and microscopic assessments revealed that juglone significantly decreased colonic tissue damage and inflammation at 150 mg/kg. Juglone at 100, 150 mg/kg significantly decreased the TNF-α, MPO, and TLR-4 levels, as well as the SOD activity. All juglone-treated groups reduced the NF-κB levels compared to the control group (p < 0.001). The compound decreased the IL-1ß, and ROS levels at the concentration of 150 mg/kg. Juglone attenuated colitis symptoms, reduced inflammation cytokines, declined neutrophil infiltration, and suppressed IL- 1ß and TNF-α expressions in acetic acid-induced colitis rats. It may be proposed that juglone improved colitis in animal model through suppression of inflammatory parameters and downregulation of the NF-κB-TLR-4 pathway. CONCLUSION: Juglone exhibited anti-inflammatory and antioxidant effects in the experimental colitis model and could be a therapeutic candidate for IBD. Juglone should be a subject for further animal and clinical trials in IBD models and for safety concerns.

Formulation and optimization of theophylline-loaded enteric-coated spanlastic nanovesicles for colon delivery; Ameliorate acetic acid-induced ulcerative colitis.

Treatment of colon diseases presents one of the most significant obstacles to drug delivery due to the inability to deliver sufficient drug concentration selectively to the colon. The goal of the proposed study was to develop, optimize, and assess an effective colon target delivery system of theophylline-based nanovesicles (TP-NVs) surrounded by a biodegradable polymeric shell of chitosan (CS) and Eudragit L100 (EL100) for the treatment of ulcerative colitis (UC). TP-loaded nanovesicles were fabricated using the ethanol injection method and coated with CS and EL100, respectively. We used a 32-factorial design approach to optimize the concentration of CS and EL100 to minimize particle size (PS) and maximize the cumulative amount of theophylline released (CTR) after 24 h. The optimized formulation was described using transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and in vitro release. In-vivo quantification of theophylline in the gastrointestinal tract and in-vivo targeting potential in a rat model of acetic acid-induced colitis were also thoroughly evaluated. The characteristics of the optimal formula predicted by the 32-factorial design approach corresponded exceptionally well with the measured PS of 271.3 nm, the zeta potential of -39.9 mV, and CTR of 3.95, and a 99.93% after 5 and 24 h, respectively. Notably, the in vivo results in the rat model of colitis showed that the formulation with an optimized coat significantly improved theophylline distribution to the colon and markedly decreased the expression of interleukin-6 and ulcerative lesions compared to a pure theophylline solution. These outcomes elucidated the feasibility of a 32-factorial design to detect the crucial interactions between the study's components. Our findings suggested that enteric-coated nanovesicles formulations with optimal coat compositions of 0.2693% (w/v) and 0.75% (w/v) of CS and EL100, respectively, were promising carriers for colonic delivery of theophylline, a rate-limiting step in the treatment of UC.

The possible effect of lycopene in ameliorating experimentally induced ulcerative colitis in adult male albino rats (A histological, immunohistochemical, and ultrastructural study).

Ulcerative colitis (UC) is considered a long-term inflammatory disorder worldwide. Its pathogenesis is associated with reduced antioxidant capacity. Lycopene (LYC) is a powerful antioxidant with strong free radical scavenging property. The present work has done to assess changes of colonic mucosa in induced UC and the possible ameliorative effects of LYC. Forty-five adult male albino rats were randomly divided into four groups: group I (control), group II was given 5 mg/kg/day (LYC) by oral gavage for 3 weeks. Group III (UC) was received single intra-rectal injection of acetic acid. Group IV (LYC+UC) received LYC in same dose and duration as before and acetic acid on 14th day of the experiment. UC group showed loss of surface epithelium with destructed crypts. Congested blood vessels with heavy cellular infiltration were observed. Significant decrease in goblet cell numbers and the mean area percentage of ZO-1 immunoexpression were noticed. Significant increase in the mean area percentage of collagen and the mean area percentage of COX-2 were also noticed. Ultrastructural changes were matched with light microscopic results that showed abnormal destructive columnar and goblet cells. Histological, immunohistochemical, and ultrastructural findings in group IV supported the ameliorative role of LYC against destructive changes induced by UC.

Gut-Kidney Impairment Process of Adenine Combined with Folium sennae-Induced Diarrhea: Association with Interactions between Lactobacillus intestinalis, Bacteroides acidifaciens and Acetic Acid, Inflammation, and Kidney Function.

BACKGROUND: Extensive evidence suggests that gut microbiota may interact with the kidneys and play central roles in the pathogenesis of disease. However, the association of gut microbiota-kidneys in diarrhea remains unclear. METHODS: A diarrhea mouse model was constructed by combining adenine with Folium sennae. We analyzed the characteristics of the gut content microbiota and short chain fatty acids (SCFAs); and explored the potential link between gut content microbiota, SCFAs, intestinal inflammatory response and kidney function. RESULTS: Characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens were enriched in the gut contents of mice. The productions of SCFAs were remarkably inhibited. Model mice presented an increased trend of creatinine (Cr), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), a decreased trend of blood urea nitrogen (BUN) and secretory immunoglobulin A (SIgA). The pathological analysis proved obvious damage to the kidney structure. Lactobacillus intestinalis and Bacteroides acidifaciens exisited in the correlations with acetic acid, intestinal inflammatory response and kidney function. CONCLUSIONS: Adenine combined with Folium sennae-induced diarrhea, altered the structure and function of the gut content microbiota in mice, causing the enrichment of the characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens. The interactions between Lactobacillus intestinalis, Bacteroides acidifaciens and acetic acid, intestinal inflammation, and kidney function might be involved in the process of gut-kidney impairment in adenine, combined with Folium sennae-induced diarrhea.

Histone deacetylase inhibitor givinostat has ameliorative effect in the colitis model.

PURPOSE: To investigate the effect of givinostat treatment in acetic acid-induced ulcerative colitis model in rats. METHODS: Thirty male Wistar albino rats were used. Rats were randomly divided into three equal groups, and colitis was induced on 20 rats by rectal administration of %4 solutions of acetic acid. Twenty rats with colitis were randomly divided into two groups. %0.9 NaCl (saline) solution was administered intraperitoneally to the first group of rats (saline group, n=10) at the dose of 1 mL/kg/day. Givinostat was administered intraperitoneally to the second group rats (Givinostat group, n=10) at the dose of 5 mg/kg/day. Samples were collected for biochemical analysis. Colon was removed for histopathological and biochemical examinations. RESULTS: Plasma tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), and malondialdehyde levels were significantly decreased in the givinostat group compared to the saline group (p<0.05, p<0.001, and p<0.001 respectively; p<0.001, p<0.001, and p<0.001, respectively). Colon TNF-α and prostaglandin F2 alpha (PGF-2) levels were significantly decreased (p<0.05, and p<0.001, respectively). The givinostat group had a significantly lower histologic score than saline group (p<0.001, and p<0.001, respectively). CONCLUSIONS: Givinostat, a good protector and regenerator of tissue and an anti-inflammatory agent, may be involved in the treatment of colitis in the future.

KPR-5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats.

AIMS: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. METHODS: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid. RESULTS: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. CONCLUSION: The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.

Fructus Mume (Wu Mei) Attenuates Acetic Acid-Induced Ulcerative Colitis by Regulating Inflammatory Cytokine, Reactive Oxygen Species, and Neuropeptide Levels in Model Rats.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder of the large intestine. Fructus mume (FM), a natural food with nutritive and pharmaceutical value, has demonstrated therapeutic efficacy against UC. In this study, we investigated the protective effects and mechanisms of FM against UC. We induced UC in rats with 4% (v/v) acetic acid (AA), orally administered 0.7 or 0.325 g/kg FM and 0.3 g/kg sulfasalazine (SASP) for 7 days, and explored the responses the drugs elicited in the rats. We assessed the general conditions of the rats by the disease active index. We evaluated colon tissue damage macroscopically and by Hematoxylin & Eosin, Alcian Blue-periodic acid-Schiff, and Masson's staining, and explored the potential mechanisms of FM on inflammation, oxidative stress, and neuropeptides by measuring TNF-α, IL-6, IL-8, IL-10, MMP9, CXCR-1, SOD, GSH-px, MDA, ROS, SIRT3, SP, VIP, ghrelin, and 5-HT. FM treatment significantly attenuated colon damage and submucosal fibrosis compared with the model. It lowered serum proinflammatory TNF-α, IL-8, and colonic MMP9 and CXCR-1, and raised serum anti-inflammatory IL-10 levels. FM upregulated the antioxidant enzymes SOD, GSH-px, and SITR3 protein but inhibited ROS and MDA production. It downregulated colonic SP, VIP, ghrelin, and 5-HT. The beneficial effects of FM might be dose dependent. Around 0.7 g/kg FM and SASP displayed similar efficacy for treating AA-induced colitis in rats. Our results provide empirical evidence that FM protects against AA-induced UC in rats via anti-inflammatory and antioxidant mechanisms, and regulates neuropeptides; thus, FM may be a promising, safe, and efficacious alternative therapy for UC, if its efficacy can be confirmed in human trials.

Anti-inflammatory, Analgesic, and Cytotoxic Effects of The Phytexponent: A Polyherbal Formulation.

The Phytexponent is used to treat pain and inflammation in complementary and alternative medicine practices; however, empirical data supporting its pharmacological efficacy and safety is scanty, hence the present study. We used the carrageenan-induced paw oedema and the acetic acid-induced writhing techniques to determine the anti-inflammatory and analgesic efficacies, respectively, of the Phytexponent in Swiss albino mice models. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay technique was used to investigate the in vitro cytotoxic effects of the Phytexponent in the Vero E6 cell line. The Phytexponent exerted significant (P < .05) anti-inflammatory effects in the carrageenan-induced paw oedema mouse model in a dose- and time-dependent manner, with significantly higher efficacy at 250 mg/Kg BW, than indomethacin (4 mg/Kg BW), in the first, second, and third hour (P < .05). Besides, the Phytexponent significantly reduced the acetic acid-induced writhing frequency in mice (P < .05), in a dose-dependent manner, depicting its analgesic efficacy. Notably, the Phytexponent (at doses: 125 mg/Kg BW and 250 mg/Kg BW) exhibited significantly higher analgesic efficacy than the Indomethacin (P<.05). Moreover, the Phytexponent was not cytotoxic to Vero E6 cells (CC50 >1000 µg/ml) compared to cyclophosphamide (CC50 = 2.48 µg/ml). Thus, the Phytexponent has significant in vivo anti-inflammatory and analgesic efficacy in mice models and is not cytotoxic to Vero E6 cell line, depicting its therapeutic potential upon further empirical investigation.

Acetic acid and the skin: a review of vinegar in dermatology.

Vinegar is commonly used as a home remedy for many skin problems. It is important for dermatologists to understand the evidence supporting its use in skin disease, as well as potential adverse effects, so they can properly counsel patients on the safe use of this widely available treatment. Vinegar possesses antimicrobial and antioxidant properties that provide utility in wound care as well as bacterial and fungal infections. There is also evidence to support its use in pruritus, head lice removal, and treatment of striae gravidarum. While generally safe, inappropriate use can result in damage to the skin. In this review, we discuss the evidence supporting vinegar as a treatment for skin disease, as well as adverse events reported from misuse, to provide dermatologists the knowledge to counsel patients on the safe and appropriate use of vinegar.

Reduce the Changes in Histological Features of Colon Resulting from Induced Ulcerative Colitis in Mice by Worm Antigens.

Ulcerative colitis is one of the inflammatory bowel disease (IBD) consequences characterized by chronic inflammation of the gastrointestinal (GI) tract. The current study aims to determine the changes in colon tissue caused by induced Ulcerative Colitis and reduce these changes by worms' antigen. The study included 45 adult male albino mice (Mus musculus), with ages ranging between 8-10 weeks; the average weights ranged between 18-32 g. Ulcerative colitis was induced by intracolonic administration of 100 µL of 4% after they had been starved for 18 h. The animals were dissected after one week, and routine histological sections were conducted. The results of the histological study showed that in the colon of white mice treated with 4% acetic acid occurred, many histological changes were represented by the appearance of inflammatory cells in the mucous layer around the goblet cells, and the formation of vacuoles, necrosis at epithelium and intense congestion under the surface epithelium. The marked histological sections of the colon in mice with induced ulcerative colitis treated with helminth extract at a concentration of 0.1 mg/kg for a week, were showed that the histological changes began to decrease in the colon tissue, with the presence of a few inflammatory cells as well as little mucus secretion.

Accidental ingestion of concentrated white vinegar in Hatay children in Turkey.

White vinegar which contains high concentrations (~85 %) of acetic acid is a staple ingredient used in food preparation in many Mediterranean cuisines but in small amounts. Being corrosive, it can cause ulcerative injury to the oropharynx and oesophagus and upset the stomach with resulting nausea and vomiting. This study presents 11 cases of paediatric patients (five boys and six girls, aged between 11 and 89 months) with oesophageal strictures who drank white vinegar by accident. They all received endoscopic oesophageal dilation (with a bougie) ranging from one to 28 per patient, depending on the severity of the injury. Follow-up showed uneventful healing in eight patients, who at the time of the telephone call were able to swallow solids and liquids normally. Two patients who could not be reached by telephone were found healthy by consulting the national database (e-Nabiz). Unfortunately, one patient, who was discharged without any symptoms after the first dilation, suffered massive gastrointestinal bleeding 24 hours after the dilation and died. The loss of this patient shows that ingesting white vinegar can be very dangerous in children, especially if parents delay seeking medical help. We believe that controlling the production and sales of highly concentrated white vinegar and selling it in child-proof containers can help to prevent accidental ingestions by children and tragic outcomes such as the one reported here.

Mesenchymal stem cells have ameliorative effect on the colitis model via Nrf2/HO-1 pathway

Purpose: To evaluate the ameliorative effect of mesenchymal stem cells (MSCs) on acetic acid colitis model via Nrf2/HO-1 pathway in rats. Methods: In this study, 30 rats were divided into three groups. Acute colitis was induced by rectal administration of 4% solution of acetic acid. MSCs were injected intraperitoneally in the treatment group. Results: Increased levels of tumor necrosis factor-α (TNF-α), pentraxin-3, and malondialdehyde (MDA) in colitis group were revealed biochemically. Increased level of TNF-α and decreased levels of Nrf2 and interleukin-10 (IL-10) were observed in rectum tissues. Increased fibrous tissue proliferation, vascularization and inflammatory cell infiltration were described in the colitis group. Significant improvement was observed in MSCs treated group histopathologically. Increased immunopositivity of TNF-α, vascular endothelial growth factor (VEGF) and CD68 markers was observed in the colitis group cells, and decreased level of this positivity was observed in MSCs treated group. Conclusions: Biochemical, histopathological and immunohistochemical results strongly support the ameliorative effect of MSCs against acetic induced colitis model via Nrf2/HO-1 pathway in rats.

A novel role of pirfenidone in attenuation acetic acid induced ulcerative colitis by modulation of TGF-ß1 / JNK1 pathway.

Colon diseases are a major health burden, particularly ulcerative colitis, in both men and women worldwide. Environmental and genetic factors in various colonic pathologies influence the onset and outcome of diseases. As the evidence from recent research is considered, the importance of inflammation in the onset, progression, and outcome is gaining more traction. The goal of this study was to see if pirfenidone could treat ulcerative colitis (UC) and if so, what mechanisms were involved. By intracolonic instillation [2 ml, 3 percent v/v acetic acid (AA)], ulcerative colitis was induced. Pirfenidone was administered to rats in different experimental groups (125 or 250 and 500 mg/kg, orally) for two weeks. Compared to normal group, the AA group showed an increase in colon weight, length, body weight, clinical evaluation, and macroscopic scoring of UC, serum lactate dehydrogenase, C-reactive protein, malondialdehyde, while decreasing serum total antioxidant capacity. Significant increases in colon Jun N terminal kinase1 (JNK1), transforming growth factor-beta (TGF-ß1), interleukin 1 beta (IL1ß), and Caspase-3 content. Furthermore, immunohistochemical staining revealed increased nuclear factor kappa B (NF-κB) expression along with histopathological changes. Pirfenidone inhibited inflammatory biomarkers release and restored oxidants/antioxidants hemostasis. In a dose-dependent manner, pirfenidone treatment showed a significantly decrease in all of these parameters. In addition, pirfenidone has significantly preserved the histopathological architecture of tissues. Current data demonstrate that Pirfenidone protects against AA-induced UC by modulating the TGF-ß1/JNK1 and Caspase-3 pathways. Pirfenidone's antioxidant, anti-inflammatory, and anti-apoptotic properties are thought to be responsible for its therapeutic benefit.

Yeast adaptive response to acetic acid stress involves structural alterations and increased stiffness of the cell wall.

This work describes a coordinate and comprehensive view on the time course of the alterations occurring at the level of the cell wall during adaptation of a yeast cell population to sudden exposure to a sub-lethal stress induced by acetic acid. Acetic acid is a major inhibitory compound in industrial bioprocesses and a widely used preservative in foods and beverages. Results indicate that yeast cell wall resistance to lyticase activity increases during acetic acid-induced growth latency, corresponding to yeast population adaptation to sudden exposure to this stress. This response correlates with: (i) increased cell stiffness, assessed by atomic force microscopy (AFM); (ii) increased content of cell wall ß-glucans, assessed by fluorescence microscopy, and (iii) slight increase of the transcription level of the GAS1 gene encoding a ß-1,3-glucanosyltransferase that leads to elongation of (1→3)-ß-D-glucan chains. Collectively, results reinforce the notion that the adaptive yeast response to acetic acid stress involves a coordinate alteration of the cell wall at the biophysical and molecular levels. These alterations guarantee a robust adaptive response essential to limit the futile cycle associated to the re-entry of the toxic acid form after the active expulsion of acetate from the cell interior.

Acetic acid treatment causes renal inflammation and chronic kidney disease in mice.

We established a novel mouse model of chronic kidney disease (CKD) using acetic acid and compared it with the 5/6-nephrectomized mouse model. In our novel model, significant increases were observed in blood biochemical values and urinary parameters. Moreover, a decrease in creatinine clearance (Ccr) was observed. This model also demonstrated a higher survival rate than the 5/6-nephrectomized model. Observed histological changes in our model included cell infiltration in the renal interstitium, tubular dilation, regenerated tubules, and glomerulosclerosis. Inflammation of the renal interstitium was particularly remarkable. TNF-α, IL-1ß, and ICAM-1 mRNA expression were up-regulated prior to elevation of mean blood pressure and prior to changes in blood biochemical values and urinary parameters. Up-regulation of TGF-ß mRNA and down-regulation of nephrin mRNA were also observed at 12 weeks after acetic acid treatment. However, no correlation between the progression of CKD and the decrease in renal blood flow was observed. Finally, repeated losartan administration attenuated the effects of acetic acid-induced renal injury. Our findings suggest that chronic kidney conditions associated with this model may be triggered by interstitial inflammation. Moreover, we suggest that this model is useful for understanding the pathophysiological mechanisms of CKD, and for evaluating the effects of therapeutic agents.