Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Functional Brain Networks of Minor and Well-Structured Major Hallucinations in Parkinson's Disease.

BACKGROUND: Minor hallucinations (mHs) and well-structured major hallucinations (MHs) are common symptoms of Parkinson's disease (PD) psychosis. OBJECTIVES: To investigate the resting-state networks (RSNs) in patients with PD without hallucinations (PD-nH), with mH (PD-mH), and with MH (PD-MH). METHODS: A total of 73 patients with PD were enrolled (27 PD-nH, 23 PD-mH, and 23 PD-MH). Using seed-based functional connectivity analyses, we investigated the RSNs supposedly related to hallucinations in PD: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), ventral attention network (VAN), and visual network (VN). We compared the cognitive function and RSN connectivity among the three groups. In addition, we performed a seed-to-seed analysis to examine the inter-network connectivity within each group using the corresponding RSN seeds. RESULTS: PD-MH group had lower test scores for attention and visuospatial functions compared with those in the other groups. The connectivity of the right intracalcarine cortex within the DAN was lower in the PD-MH group than in the others. The PD-mH and PD-MH groups showed higher connectivity in the left orbitofrontal cortex within DMN compared with the PD-nH group, whereas the connectivity was lower in the right middle frontal gyrus (MFG) within ECN, precuneus cortex within VAN, right middle temporal gyrus and precuneus cortex within DAN, and left MFG within VN. The PD-mH and PD-MH groups showed different inter-network connectivity between the five RSNs, especially regarding DAN connectivity. CONCLUSIONS: DAN dysfunction may be a key factor in the progression from mH to MH in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Fulvestrant alleviates cisplatin-induced acute kidney injury via repression of BNIP3-mediated apoptosis and autophagy.

Cisplatin-induced acute kidney injury (AKI) is a clinical disease characterized by a sudden loss of renal function within a few hours or days, due to cisplatin uptake. Fulvestrant is an oestrogen receptor alpha (ERα) antagonist used for endocrine therapy. However, the role of fulvestrant in cisplatin-induced AKI remains unclear. In this study, we investigated the effects of fulvestrant on the regulation of apoptotic cell death and autophagic response in cisplatin-induced AKI. The human kidney proximal tubule epithelial cell line (HK-2) was co-treated with fulvestrant and cisplatin. C57BL/6 mice were subcutaneously injected with fulvestrant and cisplatin was administered via intraperitoneal injection. First, cisplatin treatment increased ERα expression, apoptosis, and autophagy in HK-2 cells. Fulvestrant treatment decreased apoptosis and autophagy, which were accompanied by cisplatin treatment in HK-2 cells. Consistent with in vitro results, cisplatin treatment significantly increased ERα expression in vivo. Additionally, cisplatin treatment increased renal injury, apoptosis, and autophagy. Surprisingly, compared to that in the cisplatin-treated mice group, reduced cisplatin-induced renal injury, apoptosis, and autophagy was observed in the cisplatin+fulvestrant-treated mice group. In summary, these results suggest that fulvestrant plays an important role in cisplatin-induced AKI by decreasing apoptosis and autophagy.

Association Between White Matter Networks and the Pattern of Striatal Dopamine Depletion in Patients With Parkinson Disease.

OBJECTIVES: Individual variability in nigrostriatal dopaminergic denervation is an important factor underlying clinical heterogeneity in Parkinson's disease (PD). This study aimed to explore whether the pattern of striatal dopamine depletion was associated with white matter (WM) networks in PD. METHODS: A total of 240 newly diagnosed PD patients who underwent 18F-FP-CIT PET scans and brain diffusion tensor imaging at initial assessment were enrolled in this study. We measured 18F-FP-CIT tracer uptake as an indirect marker for striatal dopamine depletion. Factor analysis-derived striatal dopamine loss patterns were estimated in each patient to calculate the composite scores of four striatal subregion factors (caudate, more- and less-affected sensorimotor striata, and anterior putamen) based on the availability of striatal dopamine transporter. The WM structural networks that were correlated with the composite scores of each striatal subregion factor were identified using a network-based statistic analysis. RESULTS: A higher composite score of caudate (i.e., relatively preserved dopaminergic innervation in the caudate) was associated with a strong structural connectivity in a single subnetwork comprising the left caudate and left frontal gyri. Selective dopamine loss in the caudate was associated with strong connectivity in the structural subnetwork whose hub nodes were bilateral thalami and left insula, which were connected to the anterior cingulum. However, no subnetworks were correlated with the composite scores of other striatal subregion factors. The connectivity strength of the network with a positive correlation with the composite score of caudate affected the frontal/executive function either directly or indirectly through the mediation of dopamine depletion in the caudate.

Potential Link Between Cognition and Motor Reserve in Patients With Parkinson's Disease.

OBJECTIVE: To investigate whether there is a link between cognitive function and motor reserve (i.e., individual capacity to cope with nigrostriatal dopamine depletion) in patients with newly diagnosed Parkinson's disease (PD). METHODS: A total of 163 patients with drug-naïve PD who underwent 18F-FP-CIT PET, brain MRI, and a detailed neuropsychological test were enrolled. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We performed correlation analyses between motor reserve estimates and cognitive composite scores. Diffusion connectometry analysis was performed to map the white matter fiber tracts, of which fractional anisotropy (FA) values were well correlated with motor reserve estimates. Additionally, Cox regression analysis was used to assess the effect of initial motor reserve on the risk of dementia conversion. RESULTS: The motor reserve estimate was positively correlated with the composite score of the verbal memory function domain (γ = 0.246) and with the years of education (γ = 0.251). Connectometry analysis showed that FA values in the left fornix were positively correlated with the motor reserve estimate, while no fiber tracts were negatively correlated with the motor reserve estimate. Cox regression analysis demonstrated that higher motor reserve estimates tended to be associated with a lower risk of dementia conversion (hazard ratio, 0.781; 95% confidence interval, 0.576-1.058). CONCLUSION: The present study demonstrated that the motor reserve estimate was well correlated with verbal memory function and with white matter integrity in the left fornix, suggesting a possible link between cognition and motor reserve in patients with PD.

Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α.

Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.

Silencing of LLGL2 Suppresses the Estradiol-Induced BPH-1 Cell Proliferation through the Regulation of Autophagy.

Lethal giant larvae (Lgl) is an apical-basal polarity gene first identified in Drosophila. LLGL2 is one of the mammalian homologs of Lgl. However, little is known about its function in the prostate. In this study, to explore the new role of LLGL2 in the prostate, we examined the proliferative activity of a BPH-1 cell line, a well-established model for the human prostate biology of benign prostatic hyperplasia (BPH). The expression of LLGL2 was dose-dependently increased in BPH-1 cells after treatment with 17ß-estradiol (E2). Additionally, E2 treatment increased the proliferation of the BPH-1 cells. However, the knockdown of LLGL2 with siRNA significantly suppressed the proliferation of the E2-treated BPH-1 cells. Moreover, si-llgl2 treatment up-regulated the expression of LC-3B, ATG7, and p-beclin, which are known to play a pivotal role in autophagosome formation in E2-treated BPH-1 cells. Overexpression of LLGL2 was able to further prove these findings by showing the opposite results from the knockdown of LLGL2 in E2-treated BPH-1 cells. Collectively, our results suggest that LLGL2 is closely involved in the proliferation of prostate cells by regulating autophagosome formation. These results provide a better understanding of the mechanism involved in the effect of LLGL2 on prostate cell proliferation. LLGL2 might serve as a potential target in the diagnosis and/or treatment of human BPH.

Identifying the white matter structural network of motor reserve in early Parkinson's disease.

INTRODUCTION: Motor reserve refers to the individual capacity to cope with nigrostriatal dopamine depletion in Parkinson's disease (PD). This study aimed to explore the white matter structural network associated with motor reserve in patients with newly diagnosed PD. METHODS: A total of 238 patients with early-stage drug-naïve PD who underwent 18F-FP-CIT PET and brain MRI scans at initial assessment were enrolled. We estimated individual motor reserve based on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores and dopamine transporter availability in the posterior putamen using a residual model. Then, we performed threshold-free network-based statistics (TFNBS) analysis to identify the structural brain network associated with the estimated motor reserve. We also assessed the effect of the network connectivity strength on the longitudinal increase in levodopa-equivalent dose (LED). RESULTS: The mean age at PD symptom onset was 69.10 ± 9.03 years and the mean UPDRS-III score at the time of PD diagnosis was 22.44 ± 9.72. TFNBS analysis identified a motor reserve-associated structural network whose nodes were mainly in the frontal region and cerebellum. Higher network strength (i.e., greater motor reserve) was associated with a slower longitudinal increase in LED during a 3-year follow-up period. CONCLUSION: The structural brain network is associated with motor reserve in patients with PD. Connectivity strength within the identified network indicates the individual's capacity to tolerate PD-related pathologies, which is maintained with disease progression and affects the long-term motor prognosis of PD.

The extract of Celtis choseniana Nakai alleviates testosterone-induced benign prostatic hyperplasia through inhibiting 5α reductase type 2 and the Akt/NF-κB/AR pathway.

Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.

Behavioral Reserve in Behavioral Variant Frontotemporal Dementia.

"Reserve" refers to the individual clinical differences in response to a neuropathological burden. We explored the behavioral reserve (BR) and associated neural substrates in 40 participants with behavioral variant frontotemporal dementia (bvFTD) who were assessed with the frontal behavioral inventory (FBI) and magnetic resonance imaging. Because neuroimaging abnormality showed a high negative correlation with the FBI negative (but not positive) symptom scores, we developed a linear model only to calculate the nBR (BR for negative symptoms) marker using neuroimaging abnormalities and the FBI score. Participants were divided into high nBR and low nBR groups based on the nBR marker. The FBI negative symptom score was lower in the high nBR group than in the low nBR group having the same neuroimaging abnormalities. However, the high nBR group noted a steeper decline in cortical atrophy and showed less atrophy in the left frontotemporal cortices than the low nBR group. In addition, the fractional anisotropy (FA) values were greater in the high nBR than in the low nBR group, except in the sensory-motor and occipital areas. We identified an nBR-related functional network composed of bilateral frontotemporal areas and the left occipital pole. We propose the concept of BR in bvFTD, and these findings can help predict the disease progression.

Association Between White Matter Connectivity and Early Dementia in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Several clinical and neuroimaging biomarkers have been proposed to identify individuals with Parkinson disease (PD) who are at risk for ongoing cognitive decline. This study aimed to explore whether white matter (WM) connectivity disruption is associated with dementia conversion in patients with newly diagnosed PD with mild cognitive impairment (PD-MCI). METHODS: Seventy-five patients with drug-naive PD-MCI who underwent serial cognitive assessments during the follow-up period (>5 years) were enrolled for the neuroimaging analyses. The patients were classified into either the PD with dementia (PDD) high-risk group (PDD-H, n = 38) or low-risk group (PDD-L, n = 37), depending on whether they converted to dementia within 5 years of PD diagnosis. We conducted degree-based statistic analyses based on a graph-theoretical concept to identify the subnetworks whose WM connectivity was disrupted in the PDD-H group compared with the PDD-L group. RESULTS: The PDD-H group showed poorer cognitive performance on frontal/executive, visual memory/visuospatial, and attention/working memory/language function than the PDD-L group at baseline assessment. The PDD-H group exhibited more severely disrupted WM connectivity in both frontal and posterior cortical regions with 8 hub nodes in the degree-based statistic analysis. The strength of structural connectivity within the identified subnetworks was correlated with the composite scores of frontal/executive function domain (γ = 0.393) and the risk score of PDD conversion within 5 years (γ = -0.480). DISCUSSION: This study demonstrated that disrupted WM connectivity in frontal and posterior cortical regions, which correlated with frontal/executive dysfunction, is associated with early dementia conversion in PD-MCI. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that disrupted WM connectivity in frontal and posterior cortical regions is associated with early dementia conversion in PD-MCI.

White matter connectivity networks predict levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. OBJECTIVE: To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naïve Parkinson's disease. METHODS: We recruited 30 patients who developed levodopa-induced dyskinesia within 5 years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5 years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network- and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox- and linear-regression, respectively. RESULTS: Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. CONCLUSIONS: Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia.

Stauntonia hexaphylla Extract Ameliorates Androgenic Alopecia by Inhibiting Androgen Signaling in Testosterone-induced Alopecia Mice.

Background: Stauntonia hexaphylla has been a traditional folk remedy for alleviating fever and providing anti-inflammatory properties. Androgenetic alopecia (AGA) is the most common form mediated by the presence of the dihydrotestosterone (DHT). Objectives: In this study, we evaluated the effects of an extract of S. hexaphylla on AGA models and its mechanisms of action. Methods: We studied S. hexaphylla extract to evaluate 5α-reductase and androgen receptor (AR) levels, apoptosis, and cell proliferation in vitro and in vivo. In addition, paracrine factors for androgenic alopecia, such as transforming growth factor beta-1 (TGF-ß1) and dickkopf-a (DKK-1), were examined. Apoptosis was investigated, and the evaluation of proliferation was examined with cytokeratin 14 (CK-14) and proliferating cell nuclear antigen (PCNA). Results: In human follicular dermal papilla cells, the 5α-reductase and AR were decreased following S. hexaphylla treatment, which reduced the Bax/Bcl-2 ratio. Histologically, the dermal thickness and follicle number were higher in the S. hexaphylla groups compared with the AGA group. In addition, the DHT concentration, 5α-reductase, and AR were decreased, thereby downregulating TGF-ß1 and DKK-1 expression and upregulating cyclin D in S. hexaphylla groups. The numbers of keratinocyte-positive and PCNA-positive cells were increased compared to those in the AGA group. Conclusions: The present study demonstrated that the S. hexaphylla extract ameliorated AGA by inhibiting 5α-reductase and androgen signaling, reducing AGA paracrine factors that induce keratinocyte (KC) proliferation, and inhibition apoptosis and catagen prematuration.

Menstrual Cycle Patterns and the Prevalence of Premenstrual Syndrome and Polycystic Ovary Syndrome in Korean Young Adult Women.

Menstruation is one of the important indicators of reproductive health. Therefore, in order to improve the reproductive health of women in puberty and early adulthood, it is necessary to investigate menstrual health and symptoms. This cross-sectional descriptive correlational study was conducted to identify young women's menstrual cycle patterns, prevalence of Premenstrual Syndrome (PMS), Polycystic Ovary Syndrome (PCOS) and the relationships of health-related factors according to menstrual regularity and PCOS. 462 women participated in the first phase of the study and completed the menstrual health and health-related behaviors questionnaire. In the second phase, 88 women with irregular menstruation in phase one had blood tests taken and body composition measured. As a result, Menarche was slightly later in irregular menstruation group. Women with regular menstruation had a mean number of 11.7 menstrual cycles over the past year, 93.0% of them reported a normal menstruation cycle frequency (21-35 days), 95.2% reported a normal duration (2-7 days) and 55.9% of participants had heavy menstrual bleeding. In the irregular menstrual group, there were higher percentages of underweight and obese women as well as more women experiences weight and diet changes. The estimated prevalence rates of PMS and PCOS were 25.5%, 5.2% respectively. This study provides updated basic data about menstrual health among Korean young women but more extensive and sophisticated studies are needed in the future.

Menstrual Cycle Characteristics and Premenstrual Syndrome Prevalence Based on the Daily Record of Severity of Problems in Korean Young Adult Women.

PURPOSE: This descriptive study aimed to identify the menstrual cycle characteristics and premenstrual syndrome (PMS) prevalence in Korean young adult women using the retrospective and prospective Daily Record of Severity of Problems (DRSP). METHODS: In the first stage, participants included 151 nursing students studying in a university located in Seoul. Data were collected from April 20 to June 2, 2017, using the questionnaire on menstrual characteristics, pictorial blood assessment chart, and retrospective DRSP. In the second stage, participants included 17 students with PMS, based on the screening conducted in the first stage. Data were collected using the prospective DRSP from May 29 to 2 September 2, 2017. RESULTS: Of the study sample, 104 participants (68.9%) had regular periods. Those with regular periods had 11.97 periods annually with a menstrual cycle of 29.38 days and a period duration of 5.72 days. Fifty-five participants (37.4%) showed menorrhagia. Sixty-four participants (42.4%) were found to have PMS based on their retrospective DRSP. When the ratio of women (52.9%) with PMS shown in the prospective DRSP was used as a positive predictive value, the estimated PMS prevalence was 22.4%. CONCLUSION: This study provides clinically significant PMS prevalence among Korean young adult women, positive predictive value of the retrospective DRSP, and valid data to basically understand the menstrual cycle characteristics experienced by these women.