Risk of traumatic brain injury among patients with ADHD and their unaffected siblings.

BACKGROUND: As the relationship between attention deficit hyperactivity disorder (ADHD) and traumatic brain injury (TBI) is gaining increasing attention, the TBI risk in patients with ADHD, unaffected siblings of ADHD probands, and non-ADHD controls remains unclear. METHODS: Overall, 18,645 patients with ADHD, 18,880 unaffected siblings of ADHD probands, and 188,800 age-/sex-matched controls were followed up from enrollment to the end of 2011. The cases of TBI and TBI requiring hospitalization were identified during follow-up. RESULTS: Patients with ADHD (hazard ratio [HR]: 1.57) and unaffected siblings (HR: 1.20) had an increased risk of any TBI compared with non-ADHD controls. Surprisingly, the likelihood of developing TBI requiring hospitalization during follow-up was higher in the unaffected siblings group (HR: 1.21) than in the control group, whereas it was lower in the ADHD probands group (HR: 0.86). CONCLUSIONS: Patients with ADHD and unaffected siblings of ADHD probands were more likely to develop any TBI during follow-up than controls. Unaffected siblings of patients with ADHD exhibited the highest risk of subsequent TBI requiring hospitalization compared with patients with ADHD and healthy controls. Therefore, TBI risk in patients with ADHD and their unaffected siblings would require further investigation. IMPACT: ADHD diagnosis and ADHD trait are associated with risk of traumatic brain injury (TBI). Both patients with ADHD and their unaffected siblings were more likely to develop TBI during the follow-up compared with the control group. TBI requiring hospitalization occurred more in the sibling group than in the proband group. TBI risk should be closely monitored among unaffected siblings of patients with ADHD.

Scutellaria baicalensis Induces Cell Apoptosis and Elicits Mesenchymal-Epithelial Transition to Alleviate Metastatic Hepatocellular Carcinoma via Modulating HSP90ß.

Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we verified the inhibitory properties and the pivotal molecules regimented by Scutellaria baicalensis on advanced hepatocellular carcinoma. At first, the viability of SK-Hep-1 cells was significantly reduced under treatment of Scutellaria baicalensis extract in a dose-dependent manner without affecting the growth of normal hepatocyte. Scutellaria baicalensis extract application could remarkably cause apoptosis of SK-Hep-1 cells through p53/cytochrome C/poly-ADP ribose polymerase cascades and arrest the cell cycle at the G1/S phase by downregulating cyclin-dependent kinases. Meanwhile, administration of Scutellaria baicalensis extract remarkably attenuated the migration capability as well as suppressed matrix metalloproteinase activity of advanced hepatocellular carcinoma cells. The proteome profiles and network analysis particularly implied that exposure to Scutellaria baicalensis extract downregulated the expression of HSP90ß, and the clinical stage of hepatocellular carcinoma is also positively correlated with the HSP90ß level. Combined treatment of Scutellaria baicalensis extract and HSP90ß siRNAs could markedly enhance the ubiquitination activity and the degradation of vimentin to subsequently inhibit the metastatic property of SK-Hep-1 cells. Moreover, application of Scutellaria baicalensis extract and HSP90ß siRNAs depleted phosphorylation of AKT, which stimulated the expression of p53 and consecutively triggered cell apoptosis. These findings suggest that HSP90ß may be a prospective target for the effective therapy of advanced hepatocellular carcinoma via accelerating apoptosis of hepatocellular carcinoma cells and eliciting mesenchymal-epithelial transition with the administration of Scutellaria baicalensis extract.

Therapeutic efficacy of Scutellaria baicalensis Georgi against psoriasis-like lesions via regulating the responses of keratinocyte and macrophage.

Psoriasis is a chronic and recurrent skin problem that affects 3% of the global population. Nowadays, most medicines may not promise a complete cure for patients with psoriasis because of the development of pharmacoresistance and the side effects of drugs due to the microenvironment impact in the context of skin imbalance. Herein, we attempt to explore the pharmaceutical efficacy of Scutellaria baicalensis (S. baicalensis) in modulating the microenvironment created by macrophages and keratinocytes in psoriasis. The results indicated that treatment of S. baicalensis extract significantly reduced the thickness of epidermis and attenuated psoriatic lesions. Moreover, S. baicalensis extract obviously inhibited the activation and infiltration of macrophages by alleviating inflammatory factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). The administration of S. baicalensis extract also remarkably abolished oxidative damage upon DNA and proteins, which attributed to the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1). The network analysis of redox proteomics and cytokine profiles suggested that S. baicalensis administration regulated the specific pathways associated with oxidative stress, inflammation and cytokine signaling cascades to ameliorate the macrophage-targeted responses and subsequently arrest proliferation of keratinocytes. Collectively, our findings highlighted the importance of S. baicalensis application in reprogramming microenvironment to provide an alternative and complementary intervention for long-term psoriatic therapy.

Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host's immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.

Herbal Formula SS-1 Increases Tear Secretion for Sjögren's Syndrome.

Background: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren's syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer's test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44-4.41 mm) and 3.45 mm (95% CI, 2.32-4.59 mm), respectively, and a significant reduction in artificial tear use, which was -1.38 times/day, 95% CI, -1.95 to -0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren's syndrome.

Antioxidant properties of red raspberry extract alleviate hepatic fibrosis via inducing apoptosis and transdifferentiation of activated hepatic stellate cells.

Hepatic fibrosis is a wound-healing process caused by prolonged liver damage and often occurs due to hepatic stellate cell activation in response to reactive oxygen species (ROS). Red raspberry has been found to attenuate oxidative stress, mainly because it is rich in bioactive components. In the current study, we investigated the inhibitory effects and associated molecular mechanisms of red raspberry extract (RBE) upon activated hepatic stellate cell (aHSC) in cellular and rat models. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in the dimethylnitrosamine (DMN)-applied samples, whereas treatment of RBE significantly suppressed the activities of these enzymes. In addition, a histopathological analysis demonstrated that RBE could substantially diminish the hepatic collagen content and alpha-smooth muscle actin (α-SMA) expression induced by DMN. Administration of 250 µg/mL RBE could also arrest the growth and enhance the apoptosis of activated HSC-T6 cells, which was accompanied with elevated levels of activated caspases and poly (ADP-ribose) polymerase (PARP) cleavage. Particularly, RBE application remarkably abolished oxidative damage within the cells and reduced the carbonylation of proteins, which was attributed to the upregulation of catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Moreover, the knockdown of Nrf2 together with the RBE treatment synergistically abrogated the expression of α-SMA and promoted the level of peroxisome proliferator-activated receptor gamma (PPAR-γ), suggesting that RBE could mitigate the transdifferentiation of HSC in a Nrf2-independent manner. These findings implied that the application of RBE could effectively remove oxidative stress and relieve the activation of HSC via modulating the caspase/PARP, Nrf2/HO-1 and PPAR-γ pathways, which may allow the development of novel therapeutic strategies against chemical-caused liver fibrogenesis.

Postpartum Depression and Psychosis and Subsequent Severe Mental Illnesses in Mothers and Neurodevelopmental Disorders in Children: A Nationwide Study.

Background: The association between postpartum depression and postpartum psychosis and subsequent maternal and offspring mental disorders in Western countries has been established; however, whether the relationship can be generalized to the Asian population is unknown.Methods: Using the Taiwan National Health Insurance Research Database, this study enrolled 933,745 mother-infant pairs who delivered their first child and had no history of severe mental illness before childbirth from 2001 to 2010. Postpartum depression and postpartum psychosis were assessed in 3 periods between childbirth and 3, 6, or 12 months after childbirth. Subsequent maternal schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM code: 296 except 296.2x, 296.3x, 296.9x, and 296.82), and depressive disorder (ICD-9-CM codes: 296.2x, 296.3x, 300.4, and 311) and offspring autism spectrum disorder (ASD; ICD-9-CM code: 299) and attention-deficit/hyperactivity disorder (ADHD; ICD-9-CM code: 314) were identified during the follow-up period to the end of 2011.Results: Both postpartum depression and postpartum psychosis were found to be related to increased risks of schizophrenia, bipolar disorder, and depressive disorder in mothers, with hazard ratios (HRs) ranging between 8.80 (95% CI, 7.95-9.74) and 63.96 (95% CI, 50.39-81.18). Children exposed to maternal postpartum depression and psychosis were more likely to develop ADHD. Only postpartum depression was related to the likelihood of offspring ASD.Conclusions: Per these findings, we clinicians and health care providers should closely monitor the mental health condition of postpartum women and their children.

Increased Risk of Stroke in Patients With Obsessive-Compulsive Disorder: A Nationwide Longitudinal Study.

Background and Purpose: Patients with obsessive-compulsive disorder (OCD) tend to be comorbid with stroke-related risk factors, including obesity, hypertension, and diabetes. However, the temporal association between OCD and subsequent stroke risk is unclear. Methods: Using data collected between 2001 and 2010 by Taiwan's National Health Insurance Research Database, 28 064 adult patients with OCD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code: 300.3) and 28 064 age-, sex-, and comorbidity-matched controls were included in this study. Patients who developed ischemic (ICD-9-CM codes: 433, 434, and 435) and hemorrhagic (ICD-9-CM codes: 430, 431, and 432) stroke during follow-up (from enrollment to end of 2011) were identified. Moreover, medications used for treating OCD were assessed. Results: Patients with OCD (hazard ratio [HR], 3.02 [95% CI, 1.91­4.77]), especially middle-aged (HR, 2.66 [95% CI, 1.34­5.29]) and elderly adults (HR, 3.46 [95% CI, 1.70­7.05]), had an elevated risk of developing ischemic stroke during the follow-up period compared with non-OCD controls. The cumulative HR of hemorrhagic stroke did not differ (HR, 0.87 [95% CI, 0.42­1.80]) between the OCD and non-OCD groups. In patients with OCD, both short- (HR, 1.69 [95% CI, 0.74­3.88]; HR, 0.31 [95% CI, 0.05­1.95]) and long-term use (HR, 1.37 [95% CI, 0.60­3.16]; HR, 0.90 [95% CI, 0.22­3.76]) of OCD medications were not correlated with ischemic and hemorrhagic stroke compared with nonuse. Conclusions: Clinicians should closely monitor cerebrovascular disease and related risks in patients with OCD. The pathomechanism of OCD with an increased risk of ischemic stroke warrants further investigation.

Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure.

Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from the medicinal herb Centella asiatica, has already been demonstrated; however, its role in epilepsy-related cognitive deficits is yet to be determined. In this study, we evaluated the effects of asiatic acid on cognitive deficits in rats with kainic acid (KA)-induced seizure and explored the potential mechanisms underlying these effects. Our results revealed that asiatic acid administrated intraperitoneally 30 min prior to KA (15 mg/kg) injection ameliorated seizures and significantly improved KA-induced memory deficits, as demonstrated by the results of the Morris water maze test. In addition, asiatic acid ameliorated neuronal damage, inhibited calpain activation, and increased protein kinase B (AKT) activation in the hippocampus of KA-treated rats. Asiatic acid also increased the levels of synaptic proteins and the number of synaptic vesicles as well as attenuated mitochondrial morphology damage in the hippocampus of KA-treated rats. Furthermore, proteomic and Western blot analyses of hippocampal synaptosomes revealed that asiatic acid reversed KA-induced changes in mitochondria function-associated proteins, including lipoamide dehydrogenase, glutamate dehydrogenase 1 (GLUD1), ATP synthase (ATP5A), and mitochondrial deacetylase sirtuin-3 (SIRT3). Our data suggest that asiatic acid can prevent seizures and improve cognitive impairment in KA-treated rats by reducing hippocampal neuronal damage through the inhibition of calpain activation and the elevation of activated AKT, coupled with an increase in synaptic and mitochondrial function.

Atopic dermatitis and dementia risk: A nationwide longitudinal study.

BACKGROUND: Retrospective studies have suggested that patients with dementia have higher prevalence of atopic dermatitis (AD) than those without dementia. However, the temporal association of AD with subsequent dementia remains unknown. OBJECTIVE: To assess the temporal association of AD with subsequent dementia. METHODS: We included data of patients with AD aged 45 years and older (n = 1059) and 1:10 age, sex, residence, income, and dementia-related comorbidity-matched controls (n = 10,590) from the Taiwan National Health Insurance Research Database and reviewed their subsequent dementia development from the enrollment date to the end of 2013. RESULTS: After adjustments for dementia-related comorbidities, patients with AD were found to be more likely to develop any dementia (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.24-3.29), particularly Alzheimer's disease (HR, 3.74; 95% CI, 1.17-11.97), during the follow-up period than those in the control group. Moderate-to-severe AD was associated with a high subsequent dementia risk (HR, 4.64; 95% CI, 2.58-8.33). Sensitivity analyses with the exclusion of the first 3 (HR, 2.20; 95% CI, 1.28-3.80) or 5 (HR, 2.05; 95% CI, 1.08-3.89) years of observation revealed consistent findings. CONCLUSION: AD may be an independent risk factor for new-onset dementia. Clinicians may monitor the trajectory of neurocognitive function among elderly patients with AD. Additional studies elucidating the pathomechanisms between AD and subsequent dementia are warranted.

Timing of the Diagnoses of Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder in Taiwan.

ADHD comorbidity has been associated with delayed diagnosis of ASD, but no study has investigated this association in an Asian country. Children with ASD were included and divided into three groups: ADHD before ASD, ADHD same/after ASD, and ASD only. Timing of ASD and ADHD diagnoses were assessed. The logistic regression model was performed to investigate the likelihood of being diagnosed with ASD after 6 years of age between three groups. ADHD before ASD (OR 10.93) group was more likely to being diagnosed with ASD after 6 years of age compared with ADHD same/after ASD (OR: 1.37) and ASD only groups. ADHD comorbidity would delay the diagnosis of ASD in the general clinical settings in Taiwan.

Cardiometabolic disease risk among siblings of patients with major depressive disorder.

Studies have suggested an association between metabolic and cerebrocardiovascular diseases and major depressive disorder (MDD). However, the risk of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD remains uncertain. Using the Taiwan National Health Insurance Research Database, 22,438 unaffected siblings of patients with MDD and 89,752 age-/sex-matched controls were selected and followed up from 1996 to the end of 2011. Individuals who developed metabolic and cerebrocardiovascular diseases during the follow-up period were identified. Compared with the controls, the unaffected siblings of patients with MDD had a higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), and obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic stroke (0.6% vs. 0.4%, p < 0.005) and ischemic heart disease (2.1% vs. 1.7%, p < 0.001). Logistic regression analyses revealed that the unaffected siblings of patients with MDD were more likely to develop hypertension, dyslipidemia, ischemic stroke, and ischemic heart diseases during the follow-up period than the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases. Additional studies are required to investigate the shared pathophysiology of MDD and metabolic and cerebrocardiovascular diseases.

Bidirectional association between migraine and depression among probands and unaffected siblings: A nationwide population-based study.

BACKGROUND: Evidence suggests a bidirectional association between migraine and depression in individuals and in twins. However, whether a bidirectional association between migraine and depression also occurs among siblings (probands and unaffected nontwin siblings) remains unknown. METHODS: Using the Taiwan National Health Insurance Research Database, we examined the data of 1504 probands with migraine, 1595 unaffected siblings, and 6380 nonmigrainous controls born before 2000 to identify new-onset depression for the period between 1996 and 2011. Conversely, 31824 probands with depression, 34325 unaffected siblings, and 137300 nondepressive controls were examined for the identification of new-onset migraine. RESULTS: Logistic regression analyses demonstrated that compared with the controls, patients with migraine (odds ratio [OR]: 4.09; 95% confidence interval [CI]: 3.75-4.46) and unaffected siblings (OR: 1.40; 95% CI: 1.24-1.58) were more likely to develop depression during the follow-up period. Moreover, patients with depression and unaffected siblings had a 4.13-fold (95% CI: 3.18-5.36) and 1.45-fold (95% CI: 1.03-2.05) increased risk of migraine. DISCUSSION: The bidirectional association between migraine and depression among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation.

Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.

Association of parental depression with offspring attention deficit hyperactivity disorder and autism spectrum disorder: A nationwide birth cohort study.

BACKGROUND: Studies have indicated that parental depression was slightly related to the increased risk of offspring attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the association between exposure to parental depression at different neurodevelopmental stages (i.e., perinatal or postnatal period) and subsequent ADHD and ASD development remained uncertain. METHOD: 708,515 children born between 2001 and 2008 were screened for ADHD and ASD based on ICD-9-CM codes of 314 and 299 given by psychiatrists from their birth to the end of 2011. Paternal and maternal depression was separately assessed during five periods, namely those before pregnancy (pre-pregnancy), during pregnancy (perinatal), and <1, 1-3, and >3 years after childbirth (postnatal). Cox regression analyses were performed. RESULTS: Both paternal and maternal depression occurring in the pre-pregnancy, perinatal and postnatal periods were significantly associated with subsequent ADHD and ASD in the offspring, with hazard ratios between 1.42 (95% confidence interval [CI]: 1.35-1.49) and 2.25 (2.09-2.41). The chronicity and additive effect of paternal and maternal depression were related to increased risks of offspring ADHD and ASD. The effects of maternal depression were stronger than the effects of paternal depression for offspring ADHD (HR: 1.35, 95% CI: 1.27-1.45) and ASD (HR: 1.23, 95% CI: 1.05-1.46) risks. CONCLUSION: Both paternal depression and maternal depression in the pre-pregnancy, perinatal and postnatal periods increases offspring ADHD and ASD risks, and these risks increase further with increases in the duration of parental depression and with the additive effect of parental and maternal depression.

Characterizing the Relapse Potential in Different Luminal Subtypes of Breast Cancers with Functional Proteomics.

Poor prognosis due to the high relapse and metastasis rates of breast cancer has been particularly linked to the luminal B subtype. The current study utilized MCF-7 and ZR-75-1 to investigate various luminal subtypes of breast cancers that have discrepant expressions in the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Understanding of the differential protein profiles and the associated pathways could help alleviate the malignance and promote the long-term survival rate of breast cancer patients. Functional proteome tools were applied to comprehensively delineate the global protein alterations that reflect the varieties of biological features between the two subtypes. In this study, a total of 11 proteins with significant and meaningful changes were identified. These protein targets including PRX2, CK19, nucleophosmin and cathepsin D were mostly involved in cell differentiation or proliferation. Particularly, cathepsin D was highly expressed in the luminal B subtype. Moreover, the level of cathepsin-D was also upregulated in the clinical metastatic tissues. Accordingly, the RNA interference-mediated silencing of cathepsin D stimulated ER expression but suppressed the level of HER2. The knockdown of cathepsin D enhanced the level of ZO-1 and a remarkable decrease in N-cadherin was also detected. Again, the matrix metalloproteinases (MMP) activity was impaired under the cathepsin D abolishment. Collectively, this study represented a modality to explore novel relationships in a proteome complex and highlighted the functional roles of cathepsin D in treatment options for different subtypes of breast cancer.

Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study.

OBJECTIVE: Several studies suggested a potential role of viral infection in the pathophysiology of Parkinson's disease (PD). However, the association between herpes zoster and PD was not investigated well till now. METHODS: Using the Taiwan National Health Insurance Research Database, 13 083 patients aged ≥45 years with herpes zoster and 52 332 (1:4) age-/sex-matched controls were enrolled between 1998 and 2008 and followed to the end of 2011. Those who developed PD during the follow-up period were identified. RESULTS: The Cox regression analysis with adjustment of demographic characteristics, health system utilization, and comorbidities demonstrated that patients with herpes zoster had an increased risk (hazard ratio [HR]: 1.80, 95% confidence interval [CI]: 1.43-2.28) of developing PD in later life compared to the control group. Sensitivity tests after excluding the first year (HR: 1.50, 95% CI: 1.16-1.93) and first 2-year (HR: 1.44, 95% CI: 1.10-1.88) observation periods showed consistent results. CONCLUSIONS: Patients with herpes zoster were more likely to develop PD in later life compared to the controls. Additional studies are necessary for validating our results and to clarify the underlying pathophysiology between herpes zoster and PD.

Clinical and molecular genetic features of cerebrotendinous xanthomatosis in Taiwan: Report of a novel CYP27A1 mutation and literature review.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder associated with mutations in the CYP27A1 gene, and the genetic features of CTX in Taiwanese have not been examined before. OBJECTIVES: We report a new CTX family with a novel mutation in the CYP27A1 gene and analyze the clinical and molecular genetic features of CTX in Taiwan. METHODS: The clinical and molecular genetic features of the two siblings from the new CTX family and the other 7 reported Taiwanese CTX patients were included for analysis. The clinical features of the enrolled CTX patients were recorded using the indicators that make up the suspicion index (SI). RESULTS: The age at CTX diagnosis of the two siblings in the new CTX family were in late 30s, and predominantly psychiatric features. Both siblings had compound heterozygous splicing mutations in the CYP27A1 gene, including one mutation in exon 2 (c.435G>T, cryptic splice site) and one mutation in intron 7 (c.1264A>G, canonical splice site). None of the CTX patients in Taiwan were diagnosed during childhood or adolescence, and the most common clinical features of the 9 Taiwanese CTX patients were tendinous xanthomas, followed by ataxia and/or spastic paraparesis, dentate nuclei signal alternation at magnetic resonance imaging, intellectual disability and/or psychiatric disturbance, and polyneuropathy. Mutations in the CYP27A1 gene in the Taiwanese population were most commonly observed in exon 2, followed by exon 8 and intron 7. Except for one CTX patient who had an SI score of 100, the SI scores ranged from 300 to 400 before the study of the CYP27A1 gene and diagnosis. CONCLUSIONS: We reported two Taiwanese CTX siblings who had compound heterozygous mutations in CYP27A1. Exons 2 and 8 and intron 7 are the hotspots for Taiwanese CTX mutations. The diagnosis of CTX in Taiwan is usually delayed and is probably under-recognized based on statistical estimations. Early identification and genetic diagnosis may be helpful to CTX patients because early treatment can reduce the accumulation of cholestanol and slow disease progression.

Comparison of the Biological Impact of UVA and UVB upon the Skin with Functional Proteomics and Immunohistochemistry.

The skin provides protection against external stimuli; however, solar radiation, including ultraviolet A (UVA) and ultraviolet B (UVB), can result in profound influences on skin structure and function, which eventually impairs its molecular characteristics and normal physiology. In the current study, we performed proteome tools combined with an immunohistological approach on nude mouse skin to evaluate the adverse responses elicited by UVA and UVB irradiation, respectively. Our findings indicated that UVA significantly promotes oxidative damage in DNA, the breakdown of collagen fiber in the dermis, and the apoptosis of fibroblasts, which leads to inflammation. Meanwhile, UVB administration was found to enhance the carbonylation of various proteins and the proliferation of keratinocyte. Particularly, raspberry extract, which has been confirmed to have antioxidative efficacy, could effectively attenuate ultraviolet (UV) radiation-caused cell death. Network analysis also implied that UVA and UVB induce quite different responses, and that UVA results in cell death as well as inflammation mediated by caspase-3 and activator protein 1/nuclear factor kappa-light-chain-enhancer of activated B cells (AP-1/NF-B), while UVB predominantly increases the risk of skin carcinogenesis involved with oncogenes such as p53 and c-Myc. Taken together, functional proteomics coordinated with histological experiments could allow for a high-throughput study to explore the alterations of crucial proteins and molecules linked to skin impacts subjected to UVA and UVB exposure.

Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis.

The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs' growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades.