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Bromelain, a cysteine protease found in pineapple, has beneficial effects in the treatment of inflammatory diseases; however, its effects in cardiovascular pathophysiology are not fully understood. We investigated the effect of bromelain on atherosclerosis and its regulatory mechanisms in hyperlipidemia and atheroprone apolipoprotein E-null (apoe−/−) mice. Bromelain was orally administered to 16-week-old male apoe−/− mice for four weeks. Daily bromelain administration decreased hyperlipidemia and aortic inflammation, leading to atherosclerosis retardation in apoe−/− mice. Moreover, hepatic lipid accumulation was decreased by the promotion of cholesteryl ester hydrolysis and autophagy through the AMP-activated protein kinase (AMPK)/transcription factor EB (TFEB)-mediated upregulation of autophagy- and antioxidant-related proteins. Moreover, bromelain decreased oxidative stress by increasing the antioxidant capacity and protein expression of antioxidant proteins while downregulating the protein expression of NADPH oxidases and decreasing the production of reactive oxygen species. Therefore, AMPK/TFEB signaling may be crucial in bromelain-mediated anti-hyperlipidemia, antioxidant, and anti-inflammatory effects, effecting the amelioration of atherosclerosis.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

The awareness on ischemic heart disease (IHD) in women with dysmenorrhea is insufficient. We utilized the National Health Insurance Research Database (NHIRD) of Taiwan to evaluate this relationship. From the claims data, we established a cohort of women aged 15–50 years with primary dysmenorrhea diagnosed from 2000 to 2008 (n = 18,455) and a comparison cohort (n = 36,910) without dysmenorrhea, frequency matched by age and diagnosis date. Both cohorts were followed until the end of 2013 to assess IHD events. With 75% of study population aged 15–29 years, the incidence of IHD was greater in the dysmenorrheal cohort than in the comparison cohort (1.93 versus 1.18 per 10,000 person-years), with an adjusted hazard ratio of 1.60 (95% confidence interval [CI] = 1.38–1.85). The incidence increased with age and the rate of increase was greater in the dysmenorrheal cohort than the comparison cohort. Nested case-control analysis in the dysmenorrhea cohort showed that IHD risk was also associated with hypertension and arrhythmia, with adjusted odds ratios of 2.50 (95% CI = 1.64–3.81) and 3.30 (95% CI = 2.25–4.86), respectively. Women with dysmenorrhea are at a higher risk of developing IHD, particularly for older patients and patients with comorbidity.

Background: Studies on strokes associated with dysmenorrhea are limited. We conducted a propensity-score-matched retrospective cohort study to assess the risk of stroke in women with primary dysmenorrhea (PD). Methods: From the claims data of one million people in Taiwan’s insurance program, we identified 18,783 women aged 15–40 years, newly diagnosed with PD in 2000–2010, without a history of stroke. We randomly selected a comparison cohort without stroke history and dysmenorrhea, with the same sample size matched by age, index date, and propensity score. We began a follow-up with individuals one year after cohort entry to the end of 2013 to capture stroke events. Results: The two study cohorts were well-matched for age and comorbidities, with 54% of women aged 15–24. Stroke incidence was 1.5-fold higher in the PD cohort than in the comparison cohort (6.05 vs. 4.01 per 10,000 person-years, or 99 vs. 65 cases), with an adjusted hazard ratio (aHR) of 1.51 (95%CI 1.11–2.06) after adjustment for matched pairs. Nearly 70% of strokes were ischemic strokes, which occurred 1.6 times more frequently in the PD cohort than in the comparison cohort (4.40 vs. 2.71 per 10,000 person-years, or 72 vs. 44 cases), aHR = 1.61 (95% CI 1.11–2.33), after adjustment for matched pairs. The incidence of hemorrhagic stroke was also higher in the PD cohort than in the comparison cohort (1.65 vs. 1.29 per 10,000 person-years, or 27 versus 21 cases), but the difference was not significant. Conclusion: Women of reproductive age with PD are at increased risk for ischemic stroke.

Postherpetic neuralgia (PHN) is a common, painful, and long-term complication of herpes zoster (HZ). PHN increases the demand for healthcare services and, previous studies showed that patients who received antiviral agents were less likely to develop PHN. The objective of this study was to compare the efficacy of prodrugs and acyclovir in treating PHN among patients with HZ. The search included the PubMed, Medline, Embase, and Cochrane Center of Register of Controlled Trails databases through February 2022. Clinical trials and randomized controlled trials (RCTs) involving antiviral agent intervention for HZ patients diagnosed with PHN were eligible for inclusion. A meta-analysis was conducted to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs) with a fix-effect model. Five RCTs with 1147 HZ patients met our eligibility criteria. Our meta-analysis found that there was a significantly lower risk of PHN for members of the prodrugs group (famciclovir and valaciclovir) compared with those who received acyclovir (RR = 0.86, 95%, CI: 0.75 to 0.98, p = 0.03). The review of studies indicated that the efficacy of prodrugs was better than acyclovir for reliving PHN.

Safrole is a natural compound categorized as a group 2B carcinogen extracted from betel quid chewing, which is a common practice of psychoactive habits integrated into social and cultural ceremonies among serveral million people, especially in Southern or Southeastern Asia. Safrole is one of the major risk compunds for development of oral squamous cell carcinoma and hepatocellular carcinoma via DNA adduction. In innate immunity, macrophages are the predominant cells for non-specific first line defense against pathogens in oral tissue. Up to now, there is no evidence to implicate the potential toxicological effect of safrole on macrophages. In this study, we found safrole induced the generation of reactive oxygen species (ROS) and myeloperoxidase (MPO) in RAW264.7 macrophages in a concentration-dependent manner. Furthermore, cytotoxicity, DNA damage, and apoptosis were caused by safrole in a concentration-dependent manner. While the activation of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) was reduced, the phosphorylation of Akt was induced by safrole in a concentration-dependent manner. These results indicated that the induction of cytotoxicity, DNA damage, and apoptosis in macrophages by safrole was through generation of ROS and inhibition of antioxidative enzymes possibly via Akt phosphorylation.

This study aimed to determine the mechanism of ketamine-induced cystitis without metabolism. A total of 24 adult male Sprague-Dawley rats were separated into control, ketamine, and norketamine groups. To induce cystitis, rats in the ketamine and norketamine groups were treated with intravesical instillation of ketamine and norketamine by mini-osmotic pump, which was placed in subcutaneous space, daily for 24 h for 4 weeks. After 4 weeks, all rats were subjected to bladder functional tests. The bladders were collected for histological and pathological evaluation. Compared to control, ketamine treatment demonstrated an increase in the bladder weight, high bladder/body coefficient, contractive pressure, voiding volume, collagen deposition, reduced smooth muscle content, damaged glycosaminoglycan layer, and low bladder compliance. Compared to ketamine, norketamine treatment showed more severe collagen deposition, smooth muscle loss, damaged glycosaminoglycan layer, and increased residual urine. Intravesical administration of ketamine and norketamine induced cystitis with different urodynamic characteristics. Norketamine treatment caused more severe bladder dysfunction than ketamine treatment. Direct treatment of the bladder with norketamine induced symptoms more consistent with those of bladder outlet obstruction than ketamine cystitis. Detailed studies of cellular mechanisms are required to determine the pathogenesis of ketamine cystitis.

Lipopolysaccharide (LPS), also called endotoxin, is the important pathogen of acute lung injury (ALI), which is a clinical syndrome that still lacks effective therapeutic medicine. Rutin belongs to vitamin P and possesses various beneficial effects. In this study, we investigate the potential protective effects and the mechanisms of rutin on LPS-induced ALI. Pre-administration with rutin inhibited LPS-induced arterial blood gas exchange and neutrophils infiltration in the lungs. LPS-induced expression of macrophage inflammatory protein (MIP)-2 and activation of matrix metalloproteinase (MMP)-9 were suppressed by rutin. In addition, the inhibitory concentration of rutin on phosphorylation of Akt was similar as MIP-2 expression and MMP-9 activation. In conclusion, rutin is a potential protective agent for ALI via suppressing the blood gas exchange and neutrophil infiltration. The mechanism of rutin is down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation.

Ying-Hsia Shih,1,2 Xi-Zhang Lin,3 Chung-Hsin Yeh,1 Cheng-Liang Peng,1,2 Ming-Jium Shieh,2,4 Wuu-Jyh Lin,1 Tsai-Yueh Luo1,51Isotope Application Division, Institute of Nuclear Energy Research, Longtan, 2Institute of Biomedical Engineering, National Taiwan University, Taipei, 3Department of Internal Medicine, National Cheng Kung University, Tainan, 4Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, 5Institute of Radiological Science, Central Taiwan University of Science and Technology, Taichung, TaiwanAbstract: Radiolabeled Lipiodol® (Guerbet, Villepinte, France) is routinely used in hepatoma therapy. The temperature-sensitive hydrogel polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol triblock copolymer is used as an embolic agent and sustained drug release system. This study attempted to combine the polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol hydrogel and radio-labeled Lipiodol to form a new radio-thermogelling emulsion, rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol/hydrogel (188Re-ELH). The therapeutic potential of 188Re-ELH was evaluated in a rodent hepatoma model. Rhenium-188 chelated with N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride was extracted with Lipiodol to obtain rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol (188Re-EL), which was blended with the hydrogel in equal volumes to develop 188Re-ELH. The 188Re-ELH phase stability was evaluated at different temperatures. Biodistribution patterns and micro-single-photon emission computed tomography/computed tomography images in Sprague Dawley rats implanted with the rat hepatoma cell line N1-S1 were observed after in situ tumoral injection of ~3.7 MBq 188Re-ELH. The therapeutic potential of 188Re-EL (48.58±3.86 MBq/0.1 mL, n=12) was evaluated in a 2-month survival study using the same animal model. The therapeutic effects of 188Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of 188Re-EL. The responses were assessed by changes in tumor size and survival rates. The 188Re-ELH emulsion was stable in the gel form at 25°C–35°C for >52 hours. Biodistribution data and micro-single-photon emission computed tomography/computed tomography images of the 188Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term 188Re-ELH studies have demonstrated protracted reductions in tumor volumes and positive effects on the survival rates (75%) of N1-S1 hepatoma-bearing rats. Conversely, the 2-month survival rate was 13% in the control sham group. Therapeutic responses differed significantly between the two groups (P

Endotoxins exist anywhere including in water pools, dust, humidifier systems, and machining fluids. The major causal factor is endotoxins in many serious diseases, such as fever, sepsis, multi-organ failure, meningococcemia, and severe morbidities like neurologic disability, or hearing loss. Endotoxins are also called lipopolysaccharide (LPS) and are important pathogens of acute lung injury (ALI). Rutin has potential beneficial effects including anti-inflammation, antioxidation, anti-hyperlipidemia, and anti-platelet aggregation. Pre-treatment with rutin inhibited LPS-induced neutrophil infiltration in the lungs. LPS-induced

Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK-NF-κB activation and upregulation of antioxidative enzymes.

Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ-induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ-induced expression of iNOS and COX-2 in the same concentration range. While LPS/INFγ-induced expression of P-p65 and P-IκB was inhibited by wogonin—only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ-stimulated BV2 cells is attributed mainly to interference in the Src-MEK1/2-ERK1/2-NFκB-signaling pathway. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1162–1170, 2014.

To investigate the inhibitory activities of norcantharidin (NCTD), a demethylated analogue of cantharidin, on Hep3B cells (a human hepatoma cell line) with deficiency of p53.The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined.NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G(2)M phase arrest occurs at low concentration ([Symbol: see text] 25 μmol/L) but G(0)G(1) phase arrest at high concentration (50 μmol/L). The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation.NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G(2)M or G(0)G(1) phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway.

Purpose Oxidative stress and endoplasmic reticulum (ER) stress may induce renal apoptosis and contribute to the pathogenesis of the kidney with unilateral ureteral obstruction (UUO). Materials and Methods We induced UUO the female Wistar rats by ligation of the left ureter at the ureteropelvic junction. The UUO kidney was performed from 4 hr to 7 days course. At the indicated time, we measured the arterial blood pressure and renal blood flow in each rat, renal ROS measurement in vivo by a chemiluminescence analyzer. We performed immunohistochemistry of monocyte/macrophage (ED-1) stain for leukocyte infiltration, 4-hydroxynoneal (4-HNE) stain for ROS products, and apoptosis by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and Western blot to analyze ER stress-associated and apoptosis-related proteins expression in the UUO kidney. Results We found that UUO decreased renal blood flow and increased renal vascular resistance and renal ROS. UUO decreased renal manganese superoxide dismutase (MnSOD) and catalase protein expression in a time-dependent manner. Increased 4-HNE stain in the renal tubules and ED-1 stain in the renal tubulointerstitial compartment occurred after 4 hr of UUO in the kidney. UUO significantly enhanced ER stress markers like ER stress-response protein 25 and glucose-regulated protein 78 and ER-associated apoptosis proteins, c-JUN NH2-terminal kinase, and caspase 12, in the kidney. Subsequently, UUO enhanced renal pro-apoptotic Bax and caspase 3 expression and decreased anti-apoptotic Bcl-2 expression, leading to renal tubular apoptosis. Conclusions Our data suggest that renal tubular apoptosis induced by oxidative stress and ER stress occurred in the UUO kidney. Neurourol. Urodynam. 30:472–479, 2011. © 2011 Wiley-Liss, Inc.

ObjectiveBecause of patients' fear of surgery, the psychological symbolism of the male character, and significant encouragement by urologists, the majority of patients with advanced prostate cancer prefer medical castration as a choice of hormonal treatment. We investigated how the preserved testes were affected by medical castration with luteinizing hormone-releasing hormone (LH-RH) agonist and/or antiandrogen therapy.Materials and MethodsThirty-four consecutive patients with advanced prostate cancer who underwent a bilateral epididymal-sparing orchiectomy were enrolled in this study. Before surgery, 19 of them had received LH-RH agonists and/or antian-drogens, while the other 15 patients had not. Morphological measurements were made immediately after the operation, and a histological examination was performed by a uropathologist with confirmation by urologists. The axial length, weight, and histopathological findings of the testes and prostate-specific antigen (PSA)/tes-tosterone level were compared between the two groups. Histological changes and characteristics were recorded and analyzed.ResultsThe median axial length and weight of the testes in the 19 patients with prior medical castration were 2.6 (2.0–3.6) cm and 8.0 (6.0–11.5) g, which significantly differed from those with primary surgical castration [4.0 (2.9–5.0) cm and 12.0 (9.0–17.0) g, both p< 0.001]. Moreover, profound atrophic and fibrosclerotic changes were noted in the seminiferous tubules in the group with prior medical castration. Specific findings, including basement membrane thickening and interstitial cell hyperplasia, were noted in specimens with prior medical castration. However, the postoperative serum PSA and testosterone levels did not significantly differ between the two groups.ConclusionMedical castration in patients with advanced prostate cancer indeed caused a significant reduction in the volume and profound pathological change in the testes, which may compromise a patient's expectation of his self-image (symbol of sexual virility).

Sexual health is defined by the World Health Organization as the integration of somatic, emotional, intellectual, and social aspects in ways that are positively enriching and that will enhance personality, communication, and love. The female sexual response is multifaceted and involves neurovascular, endocrine, and psychosocial factors. Optimal female sexual health comprises physical, mental, and emotional aspects, and these are the context in which a woman experiences desire, arousal, and orgasm. Sexual dysfunction in females is a complex and highly prevalent disease, and is commonly associated with the quality of life. Several factors influence female sexual function, including physiological and psychosocial factors. This article discusses models of female sexual response, defines and categorizes female sexual dysfunction, and identifies therapeutic modalities for female patients with sexual dysfunction.

To evaluate the recurrence of a bladder tumor on the prostate fossa and bladder neck in patients undergoing simultaneous transurethral resection of a bladder tumor (TUR-BT) and benign prostatic hyperplasia (BPH) in our hospital, we retrospectively studied four patients who underwent simultaneous TUR-BT and transurethral resection of the prostate (TUR-P) in 2001 to 2004. The pathology was confirmed histologically to be transitional cell carcinoma of the bladder tissue or atypia cells and BPH. Two patients had bladder tumor recurrence at 18 and 33 months during the postoperative follow-up period (10–36 months, with a mean of 18.5 months). One at the bladder neck recurred 33 months postoperatively, and the other in the trigone area, near the bladder neck, recurred after 18 months. After another TUR-BT, there were no more recurrences in these two patients. No tumor progressed to the invasive stage. Tumor recurrence on simultaneous TUR-BT and TUR-P patients is a key issue of concern. We present a brief history of the four patients and a literature review. We concluded that conducting the two procedures simultaneously is clinically feasible for selected patients.

Extrapulmonary small-cell carcinoma (EPSCC) is a rare small-cell carcinoma (SCC). It is recognized as a clinicopathological entity distinct from SCCs of the tracheobronchial tree. EPSCCs account for about 2.5% of all SCCs. SCCs of the kidney are an even rarer neoplasm. Abdominal pain and hematuria are the major clinical symptoms. Many cases are already advanced disease at diagnosis and have poor prognoses. Platinum-based chemotherapy seems to be beneficial for overall survival. We describe an 82-year-old male patient who was seen at the emergency room due to complaints of gross hematuria and right-flank pain. Computed tomography showed a large right renal tumor. Treatment modalities, pathologic features, survival outcome of this case, and a review of similar cases in the literature are presented and discussed. To the best of our knowledge, this is the 21 st case of SCC of the kidney reported in the literature to date. It is also the first report in Taiwan of a primary SCC of the kidney with the tumor thrombus extending to the inferior vena cava which required a right radical nephrectomy.