Antidepressants and Risk of Type 2 Diabetes Mellitus: A Population-Based Nested Case-Control Study.

PURPOSE/BACKGROUND: The increased risk of type 2 diabetes mellitus (T2DM) among users of antidepressants (ADs) might be mediated by depression. We investigated whether ADs are associated with increased risk of T2DM in patients with depression. Moreover, the relationship between binding affinities of serotonin transporter (SERT) of ADs and the risk of T2DM is examined. METHODS/PROCEDURES: We conducted a retrospective nested case-control study using data from Taiwan's National Health Insurance Research Database between 2000 and 2013. A total of 3038 patients with depression, 1519 cases of T2DM, and 1519 controls matched for age, sex, and index date, were included. Exposure to ADs was categorized by type and SERT. The association between AD exposure and T2DM development was assessed using conditional logistic regression analysis. FINDINGS/RESULTS: No association between T2DM development and selective serotonin reuptake inhibitors (adjusted odds ratio [AOR], 1.01; 95% confidence interval [CI], 0.87-1.19; P = 0.962), serotonin-norepinephrine reuptake inhibitors (AOR, 1.13; 95% CI, 0.94-1.37; P = 1.196), tricyclic antidepressants (AOR, 1.01; 95% CI, 0.85-1.21; P = 0.906), or others (AOR, 0.88; 95% CI, 0.75-1.03; P = 0.104) was found. Alternatively, no association between individual ADs and potency of affinity to SERT and the risk of T2DM was found. IMPLICATIONS/CONCLUSIONS: No association between ADs and increase risk of T2DM was found in patients with depression. However, regular metabolic evaluations are recommended for patients with depression regularly taking ADs.

Low Persistence of Antithrombotic Agents is Associated with Poor Outcomes after First-ever Acute Ischemic Stroke.

OBJECTIVE: This study investigated the time-trend persistence with antithrombotic agents (AT) and assessed the impact of AT persistence on outcome events and adverse events (AE) within two years after first-ever acute ischemic stroke (IS). METHODS: Using Taiwan's National Health Insurance claims dataset, 7,341 IS subjects hospitalized between 2001 and 2005 with AT prescribed at discharge and survived at least 3 months were followed up for 2 years. Time-trends of AT usage were analyzed. Medication persistence was assessed as the proportion of days covered (PDC) for filled prescription, and categorized into low, intermediate and high persistence. Multivariate logistic regression analysis and multivariate Cox proportional hazard regression models were performed to identify factors associated with AT persistence and its impact on vascular outcomes. RESULTS: AT persistence rates declined sharply from 81% to 52% during the first 6 months. In addition to patient and facility-level characteristics, occurrence of AE (e.g., GI bleeding/ulceration, fractures/ major trauma, and iatrogenic/unspecific illness) was inversely related to AT persistence. Compared with patients with low persistence, the composite risk of recurrent stroke, cardiovascular disease, or death from any cause was significantly lower in patients with intermediate (Hazard Ratio [HR] 0.64, 0.57-0.71) or high AT persistence (0.74, 0.66-0.83).

Malnutrition in Acute Stroke Patients Stratified by Stroke Severity- A Hospital Based Study.

BACKGROUND: Stroke results in high mortality with tremendous health care burden. Malnutrition is frequently observed in patients after stroke. This study was designed to explore the nutritional status in the acute stage of stroke aiming at exploring factors related to malnutrition after stroke. METHODS: This was a hospital based, prospective, observational study recruiting cerebrovascular diseases patients hospitalized for acute management. Patients suffered from all kinds of cerebrovascular diseases hospitalized for management within 30 days after onset were consecutively recruited in the study hospitals. Stroke severity was evaluated by National Institutes of Health Stroke Scale, functional status by Barthel index, and global outcome by modified Rankin Scale. Cognitive function was evaluated by Mini-Mental State Examination. Nutritional status was assessed by Mini Nutritional Assessment (MNA), stratified by 1) adequate nutritional status, MNA ≥ 24; 2) protein-calorie malnutrition, MNA less than 17; 3) at risk of malnutrition, MNA between 17 and 23.5. RESULTS: There were 231 cerebral infarction patients recruited at 13.5 days (25-75%: 5.0-17.0) after stroke onset with mild stroke severity 71.4% and severe 10.4% with nasogastric tube insertion in 14%. Malnutrition was identified in 12.1% with 54.1% at risk of malnutrition. Factor related to malnutrition was severe stroke severity with dependency. Patients with old age, hypertension, and diabetes mellitus tended to have malnutrition or risk of malnutrition. CONCLUSION: Nutritional status was poor in stroke patients across all stroke severities within weeks. Further longitudinal outcome studies to identify the poor outcome and the evolution of nutritional status are warranted.

ROS-triggered signaling pathways involved in the cytotoxicity and tumor promotion effects of pentachlorophenol and tetrachlorohydroquinone.

Free radical-triggered tissue damage is believed to play an essential role in a variety of human diseases. Pentachlorophenol (PCP) is applied as a pesticide worldwide in both industries and homes. It is used extensively as a biocide and wood preservative. Tetrachlorohydroquinone (TCHQ) was proved as a major toxic metabolite of PCP, contributing the release of free radicals during PCP metabolism. PCP has been proposed as a tumor promoter; however, only limited knowledge is available regarding the mechanisms of tumor promotion induced by PCP and its metabolite, TCHQ. A growing amount of literature suggests that a link between reactive oxygen species (ROS) and tumor promotion could exist. Herein, we summarize the findings regarding the ROS-triggered signaling pathways involved in the cytotoxicity and tumor promotion effects of PCP and TCHQ. Some of the notable findings demonstrated that TCHQ can induce DNA lesions and glutathione depletion in mammalian cells; meanwhile, oxidative stress and apoptosis/necrosis can be found both in vivo and in vitro. Interestingly, PCP and TCHQ were proved as mild tumor promoters in two-stage tumorigenesis models, in which the possible mechanism could be through ROS generation and changed Bcl-2 gene expression. We also found significant effects of antioxidants in attenuating the oxidative stress, cyto- and genotoxicity, and apoptosis/necrosis induced by PCP and/or TCHQ. In addition, mitogen-activated protein kinase (MAPK) activation is involved in PCP/TCHQ-triggered cytotoxicity, as evidenced by the finding that higher doses of TCHQ could lead to necrosis of freshly isolated splenocytes through the production of a large amount of ROS and sustained ERK activation. These results could explain partly the underlying molecular mechanisms contributing to the tumorigenesis induced by PCP. However, the detailed mechanisms of free radicals in triggering PCP/TCHQ-mediated tumor promotion and toxicity are still not completely resolved and need to be investigated further.

Holiday ratio of hospitalization and 30-day readmission rates among cancer patients after major surgery.

BACKGROUND: To determine the association of 30-day readmission with weekend discharge and the number of holiday days during a hospital stay (holiday ratio). METHODS: This retrospective cohort study used the clinical research database and cancer registry data of our hospital from January 1, 2011 to December 31, 2017. Patient characteristics, tumor factors, clinical laboratory data, and proxies of continuity of care, such as weekend discharge or holiday ratio (holiday days/total hospitalization days), received statistical analysis. Multivariate logistic regression identified the independent factors for 30-day potentially avoidable readmission rate (PAR). RESULTS: Of 1433 patients receiving tumor resection, 520 (36.29%) had colon cancer; 440 (30.70%) had head and neck cancer (HNC), and 473 (33.01%) had other cancers (lung, liver, and prostate). The rate of 30-day PAR was 6.3% for those with colon cancer, 8.6% for HNC, and 3.6% for other cancers. The 30-day PAR did not significantly differ by discharge on a weekend versus weekday for those with colon cancer (8.33% vs. 5.90%; p = 0.379), HNC (7.06% vs. 9.01%; p = 0.566), or other cancers (0.00% vs. 4.28%; p = 0.960). Colon cancer patients with holiday ratio >0.3 had a higher readmission rate (9.58% vs. 4.82%, p = 0.041). In multivariate analysis, a holiday ratio >0.3 (adjusted odds ratio 2.16; 95% Confidence Interval, 1.05-4.39) in those with colon cancer was an independent predictor of 30-day PAR. CONCLUSIONS: Weekend discharge after major surgery did not affect 30-day readmission rates in cancer patients, but the holiday ratio did affect 30-day PAR for those with colon cancer.

Risk Factors and Outcome of Acute Kidney Injury following Acute Myocardial Infarction-A Case Series Study from 2009 to 2019.

Background: Historically, acute kidney injury (AKI) has been a common severe complication of acute myocardial infarction (MI). As percutaneous coronary interventions have become more widely used, AMI outcomes have significantly improved. However, post-AMI AKI epidemiology and its associated factors are not well-understood in the age of interventional cardiology. Materials and methods: This is a retrospective study examining changes in creatinine levels in all patients admitted for AMI in a single medical center between August 2009 and February 2019. KDIGO criteria were used to define the different stages of post-AMI AKI. Results: The study included 1299 eligible cases, among which 213 (16.4%) developed AKI during AMI index admission; and 128 (60.1%), 46 (21.6%), and 39 (18.3%) were classified as KDIGO stages 1, 2, and 3, respectively. Compared with non-AKI subjects, the AKI group had a higher prevalence of non-STEMI (48.4% vs. 29.1%, p < 0.001), higher Killip class (3 or 4), and higher in-hospital mortality (15% vs. 2.5%, p < 0.001). During the index MI hospitalization, 13.6% (29/213) of the post-MI AKI patients received hemodialysis. Baseline abnormal creatinine (≥1.5 mg/dL), dyslipidemia, and more advanced KDIGO stages (2 or 3) were associated with an increased risk of requiring in-hospital hemodialysis. Moreover, a more advanced KDIGO stage (≥2) was correlated with higher all-cause in-hospital mortality. Conclusion: AMI patients remain at risk of AKI, which negatively affects their survival in the modern age.

Prognostic factors and population-based analysis of melanoma with sentinel lymph node biopsy.

Cutaneous malignant melanoma is a rare but fatal disease in East Asia. Despite its increasing incidence, a general lack of awareness about the disease was noted. This study aims to provide population-based prognostic analysis of melanoma with sentinel lymph node biopsy (SLNB) in Taiwan. We conducted this retrospective cohort study using the data from Taiwan National Health Insurance Research Database during 1997-2013. The study cohort contains 3284 patients. The 5-year survival rates of patients undergoing SLNB and not undergoing SLNB were 45.5% and 33.6%. In multivariate analysis, age ≥ 80 years [adjusted hazard ratio (aHR) = 2.15] and male (aHR = 1.19) were associated with a poorer prognosis, while high social economic status (SES) (aHR = 0.69) and undergoing SLNB (aHR = 0.84) were good prognostic factors. Old age and low SES were associated with lower percentages of patients undergoing SLNB (P < 0.001). E-value analysis suggested robustness to unmeasured confounding. In conclusion, undergoing SLNB was associated with a better prognosis. The poor prognosis of old age and low SES may be due to decreased percentages of patients undergoing SLNB. Therefore, we recommend that SLNB should be performed on patients, especially in old age or low SES, who are candidates for SLNB according to current guidelines to achieve maximal survival.

The Association between Use of Benzodiazepine Receptor Agonists and the Risk of Obstructive Sleep Apnea: A Nationwide Population-Based Nested Case-Control Study.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse. Benzodiazepine receptor agonists (BZRAs) are associated with pharyngeal muscle relaxation, increased apnea duration, and hypoxia, which might worsen OSA. This study aimed to examine the association between the use of BZRAs and the risk of OSA. The study was conducted using data from the National Health Insurance Database of Taiwan between 2002 and 2011. We only included new users who were never exposed to any BZRAs and identified 1848 participants with OSA, and 1848 matched controls. A logistic regression model was used to determine the association between the use of BZRAs and the development of OSA. BZRA exposure was divided into usage patterns, dosage, duration, and pharmacokinetic class. We found an increased risk of OSA in current users and recent past users compared with distant past users. Patients with a higher cumulative dose of BZRAs were more likely to develop OSA compared to those with a lower cumulative dose. We found an increased risk of OSA in patients treated with BZRAs, especially for current users and those with higher cumulative doses. A reduced risk of OSA was found in Z-drug users compared with benzodiazepine users.

Impact of estimated-weight-base dose of alteplase in acute stroke treatment on clinical outcome.

Dosing of recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke treatment is often based on estimated body weight (BW) worldwide in routine clinical practice due to infeasible of accurate BW measurement. The aim of our study is to explore the impact of estimated BW when dosing rt-PA in acute ischemic stroke treatment on clinical outcome. Between January 2013 to May 2018, 126 acute ischemic stroke patients received intravenous rt-PA treatment based on estimated BW dosage were recruited. All patients had actual BW measured in ward after treatment. Based on the dosage of rt-PA given, patients were categorized into three groups, standard dose (0.8-1.0 mg/kg), overdose (>1.0 mg/kg), and underdose (<0.8 mg/kg). Among all 126 patients, 101 (80.2%) patients were treated with standard dose, 12 (9.5%) patients with overdose, and 13 (10.3%) patients with underdose of rt-PA respectively. There was no significant difference between demographic characteristics, pre-morbid risk factors, National Institutes of Health Stroke Scale (NIHSS) score at 24 h, NIHSS score at discharge, modified Rankin scale (mRS) within 0 to 2 in discharge or in 3 months after the event within the three groups. There was also no significant difference in hemorrhagic transformation and symptomatic intracranial hemorrhage (SICH). In conclusion, calculation of the dose of rt-PA based upon the estimated BW to treat acute ischemic stroke patients had no negative impact on the clinical outcome in our study.

Simultaneous Reduction of Volume and Dose in Clinical Target Volume for Nasopharyngeal Cancer Patients.

PURPOSE: To compare the treatment outcome and severe late adverse effects (AEs) between conventional volume and dose (CVD) and simultaneously reduced volume and dose (SRVD) of clinical target volume treatments in patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: This retrospective cohort study enrolled patients with nonmetastatic stage II to IV nasopharyngeal cancer from a single institute. Survival endpoints and severe (≥grade 3) late AEs and comorbidity were compared between groups. The correlation of severe late AEs, comorbidity, and overall survival (OS) were evaluated using Kaplan-Meier and Cox regression methods. RESULTS: From January 2012 to June 2017, this study enrolled 178 patients, 64 in the CVD group and 114 in the SRVD group. The 2 groups did not differ significantly in patient characteristics except for mean follow-up time (37.6 vs 48.8 months; P = .01). The SRVD group did not significantly differ from the CVD group in local control survival (82.0% vs 78.4%; P = .85), regional control survival (89.9% vs 86.0%; P = .62), or disease-free survival (76.4% vs 66.9%; P = .67). The SRVD group had significantly better OS (93.9% vs 67.0%; P < .001) and salvage survival (79.3% vs 20.7%; P < .01) and a significantly lower ratio of severe lung infection (1 of 113 vs 5 of 59; P = .02). The SRVD group had a significantly lower risk of mortality (hazard ratio [HR], 0.3; P = .03). The factors associated with a significantly higher risk of mortality were N3 (regional lymph node stage status of N3) (HR, 3.0; P = .02); comorbidities of diabetes, coronary artery disease, or chronic kidney disease (grades 2-3) (HR, 3.8; P = .009), and severe lung infection (HR, 6.3; P = .007). CONCLUSIONS: Simultaneously reduced volume and dose of clinical target volumes did not impair locoregional control or disease-free survival. The benefits of SRVD treatment may include significant reduction in severe late AEs, particularly lung infection, dysphagia, and xerostomia. However, additional studies with longer patient follow-up are required to confirm these benefits.

New prediction tool-LIST-with improved prediction accuracy for 30-day readmission rates in patients with head and neck cancer after major cancer surgery.

We hope to establish a new readmission prediction score for patients with head and neck cancer (HNC) after major cancer surgery. A retrospective cohort study was conducted from the clinical and cancer registry data at Kaohsiung Veterans General Hospital. We included the data of patients with newly diagnosed HNC who underwent surgical treatment between Nov 2010 and Dec 2017. Multivariate logistic regression was performed to determine independent factors for 30-day readmission rate and establish a new prediction score. We compared the discriminatory ability of our new prediction score, HOSPTIAL score, and LACE index using linear trend chi-square test, the Akaike information criterion (AIC), and c-statistic. The 487 patients with HNC who underwent major surgery were discharged from the medical center. Of these patients, 40 (8.2%) were readmitted to the same hospital within 30 days. Our prediction score, namely LIST (representing leukocytosis, Charlson comorbidity index score of > 0, length of stay of top 33% for the total population, and advanced tumor stage) was derived through multivariate logistic regression. Compared with the HOSPITAL score and LACE index, LIST had a higher linear trend chi-square value (27.8 vs 4.3 and 6.3), higher prediction accuracy (0.743 vs 0.586 and 0.589), and lower AIC value (251 vs 274 and 272). The LIST can estimate 30-day readmission rates in patients with HNC. More intensive discharge planning and transition of care along with patient education can be applied to this high-risk group before discharge.

A national study on long-term osteoporosis therapy and risk of recurrent fractures in patients with hip fracture.

OBJECTIVE: The study aimed to evaluate the impact of osteoporosis (OP) medication persistence on subsequent fractures and all-cause mortality in patients with hip fracture. METHODS: In this retrospective cohort study, we included patients aged ≥ 40 years with fragility hip fracture from the Taiwan's National Health Insurance Research Database. OP medication persistence was categorized as yes (≥ 12 months) or no (< 12 months). A multivariate Cox proportional hazard model was used to evaluate the association between OP medication persistence and recurrent fractures (including hip, vertebral, and upper and lower limb fractures) and all-cause mortality. RESULTS: A total of 946 patients were included in the study (86.5 % of them aged ≥ 65 years) and 210 patients persistently received OP medications. Persistent OP medication use was associated with lower fracture risk (adjusted hazard ratio [aHR] = 0.64; 95 % CI = 0.41-0.99; P = .043) in the follow-up period. The strongest predictors for all-cause mortality were age ≥ 80 years (HR = 5.68, 95 % CI = 1.36-23.64, P = .017), male sex (HR = 1.55; 95 % CI = 1.18-2.03; P = .002), and Charlson Comorbidity Index ≥ 3 (aHR = 1.56; 95 % CI = 1.07-2.27; P = .022). Kaplan-Meier curves showed a lower cumulative incidence of recurrent fractures in the persistent group than that in the non-persistent group (P = .028). CONCLUSION: Persistent OP medication use was associated with a lower risk of recurrent fractures but not with mortality in patients with hip fracture.

The Trend of Aggressive Treatments in End-of-Life Care for Older People With Dementia After a Policy Change in Taiwan.

OBJECTIVES: We evaluated the trend of end-of-life healthcare utilization and life-sustaining interventions for older adults with dementia 3 to 4 years after the change in hospice policy. DESIGN: Population-based retrospective cohort study. SETTING AND PARTICIPANTS: We used the National Health Insurance Research database of enrolled patients ≥65 years of age diagnosed with dementia who died in 2010-2013 (n = 2062). METHODS: Aggressive treatments, including healthcare utilization and life-sustaining interventions, were recorded within 6 months of death. Aggressive healthcare utilization included ≥1 emergency department visits, ≥1 hospitalizations, >14 days of hospitalization, intensive care unit admission, and death in an acute care hospital. Life-sustaining interventions were enteral tube, artificial nutrition, blood transfusion, hemodialysis, invasive ventilation, and cardiopulmonary resuscitation. RESULTS: Compared with 2010‒2012, 2013 rates significantly decreased for all measures (P < .001). Composite scores of healthcare utilization and life-sustaining treatments in 2013 were significantly lower than for 2010‒2012, after controlling for confounding variables (both P < .001). CONCLUSIONS AND IMPLICATIONS: Older patients with dementia had a trend of reduced healthcare utilization and fewer life-sustaining treatments near the end of life from 2010 to 2013 after a policy change.

NF-kappaB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis.

The increased expression and cross-linking activity of tissue transglutaminase (tTG) have been demonstrated in acute liver injury and fibrosis. We focused on the molecular mechanisms that contribute to ethanol-induced tTG expression and investigated the efficacy of propolis components in preventing both the tTG expression in vitro and fibrogenesis in vivo. We demonstrate herein that both ERK1/2 and PI3K/Akt pathways can regulate the effects of ethanol on NF-kappaB-dependent transcription and these signaling pathways may be involved in activation of ethanol-mediated tTG expression. We also found that administration of pinocembrin (PIN), one of the major components of propolis, inhibited tTG activation and significantly prevented the development of thioacetamide (TAA)-induced liver cirrhosis. The present study suggests that tTG may be an important member of the cascade of factors necessary for ethanol-induced liver fibrogenesis and PIN could serve as an anti-fibrogenic agent.

[A project to improve the screening rate of pap smear for cervical cancer].

The incidence of cervical cancer in Taiwan is high and ranks as the seventh highest in the world. However, only 28.4% of the women in Kaohsiung underwent Pap smear screening. Ironically, the screening rate for female patients in our hospital was even lower at 13.2%. As medical staff in a public, community hospital, we have the responsibility to promote the health of our residents. The aim of this project was to increase the Pap smear screening rate to 28.0% in our community. The prior data analysis revealed that the low rate of Pap smear screening was related to inadequate information about the Pap smear, poor health knowledge among the women in this community, long processing time (50.86 +/- 5.88 minutes), inconvenient accessibility, and the lack of good explanation from our medical staff. The situation has significantly improved after we made adjustments including: providing an education program for women in our community, reduction of processing time, and convenient home services. The Pap smear screening rate increased from 13.2% to 28.4. The entire processing time was reduced to 20.48 +/- 2.28 minutes. We encourage women of all ages to take Pap smear tests regularly, which would be helpful for the prevention of cervical cancer.

P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment.

Cellular senescence is characterized by permanent cell cycle arrest, triggered by a variety of stresses, such as telomerase inhibition, and it is recognized as a tumor-suppressor mechanism. In recent years, telomerase has become an important therapeutic target in several cancers; inhibition of telomerase can induce senescence via the DNA damage response (DDR). Pterostilbene (PT), a dimethyl ether analog of resveratrol, possesses a variety of biological functions, including anticancer effects; however, the molecular mechanisms underlying these effects are not fully understood. In this study, we investigated the possible mechanisms of PT-induced senescence through telomerase inhibition in human non-small cell lung cancer cells and delineated the role of p53 in senescence. The results indicated that PT-induced senescence is characterized by a flattened morphology, positive staining for senescence-associated-ß galactosidase activity, and the formation of senescence-associated heterochromatic foci. Telomerase activity and protein expression was significantly decreased in H460 (p53 wild type) cells compared with H1299 (p53 null) cells and p53 knockdown H460 cells (H460-p53-). A more detailed mechanistic study revealed that PT-induced senescence partially occurred via a p53-dependent mechanism, triggering inhibition of telomerase activity and protein expression, and leading to the DDR, S phase arrest and, finally, cellular senescence. This study is the first to explore the novel anticancer mechanism of PT senescence induction via the inhibition of telomerase in lung cancer cells.

Evaluating the urate-lowering effects of different microbial fermented extracts in hyperuricemic models accompanied with a safety study.

Uric acid (UA) is an end product of purine metabolism by the enzyme xanthine oxidase (XOD). Hyperuricemia is characterized by the accumulation of serum UA and is an important risk factor for gout and many chronic disorders. XOD inhibitors or uricase (catalyzes UA to the more soluble end product) can prevent these chronic diseases. However, currently available hypouricemic agents induce severe side effects. Therefore, we developed new microbial fermented extracts (MFEs) with substantial XOD inhibition activity from Lactobacillus (MFE-21) and Acetobacter (MFE-25), and MFE-120 with high uricase activity from Aspergillus. The urate-lowering effects and safety of these MFEs were evaluated. Our results showed that MFE-25 exerts superior urate-lowering effects in the therapeutic model. In the preventive model, both MFE-120 and MFE-25 significantly reduced UA. The results of the safety study showed that no organ toxicity and no treatment-related adverse effects were observed in mice treated with high doses of MFEs. Taken together, the results showed the effectiveness of MFEs in reducing hyperuricemia without systemic toxicity in mice at high doses, suggesting that they are safe for use in the treatment and prevention of hyperuricemia.

Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells.

An animal study in rats and a cell culture study in normal human lung epithelial cells were conducted to evaluate the efficacy of N-acetyl-l-cysteine (NAC) in paraquat intoxication and associated inflammatory and oxidative stress. The effectiveness of post treatment was measured by the change of mortality rates and markers of oxidative stress, including glutathione, malondialdehyde and superoxide anion production. In addition, the levels of nitric oxide were also examined in both animal and cell culture system. NAC treatment does significantly increase the probability of survival in paraquat-intoxicated rats. It can suppress the serum malondialdehyde levels and production of superoxide anions, and conversely, augment total glutathione concentrations in all studying tissues significantly. Moreover, NAC treatment post in paraquat intoxication could reduce destruction of lung tissue, showing less inflammatory cell infiltration in interstitial stroma and mild vascular congestion. The levels of nitrite in serum and BALF were lower than those of the PQ-treated rats. Similarly, levels of iNOS expression and nitrite formation were significantly lower in normal human lung epithelial cells treated with PQ and NAC than PQ-treated alone cells.

The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death.

Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.