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.

Dietary Intake of Antioxidant Vitamins and Its Relation to the Progression of Chronic Kidney Disease in Adults With Preserved Renal Function.

OBJECTIVE: It is expected that antioxidants contribute to slow the progression of chronic kidney disease (CKD). However, there are no data on the protective effect of dietary antioxidant vitamins on CKD. The purpose of study was to evaluate the renoprotective effect of dietary antioxidant vitamins in the general population. DESIGN AND METHODS: The study participants were 127,081 Korean adults with preserved renal function with estimated glomerular filtration rate ≥60 mL/min/1.73 m2. They were categorized into 3 groups by tertile levels of dietary antioxidant vitamins intake including vitamins C, E, and A. Cox proportional hazard assumption was used to calculate multivariable hazard ratios and 95% confidence interval for the incident moderate to severe CKD (adjusted hazard ratio [95% confidence interval]) according to tertile levels of dietary intake of antioxidant vitamins. Subgroup analysis was conducted to evaluate the risk of progression from normal to mildly decreased renal function, and from mildly decreased renal function to moderate to severe CKD. RESULTS: The risk of moderate to severe CKD was not significantly associated with the third tertile of dietary antioxidant vitamin intake including vitamin C (1.02 [0.78-1.34]), E (0.96 [0.73-1.27]), and A (0.98 [0.74-1.29]). Additionally, any tertile groups didn't show the significant association with the risk of moderate to severe CKD. Subgroup analysis also didn't show the decreased risk of progression from normal to mildly decreased renal function, and from mildly decreased renal function to moderate to severe CKD in any tertile groups. CONCLUSION: Dietary intake of vitamins C, E, and A was not significantly associated with the risk of CKD progression.

Predictive ability of the Chinese visceral adiposity index for incident hypertension in working-aged Koreans.

OBJECTIVES: The Chinese visceral adiposity index (CVAI) was developed to assess visceral adipose tissue in the Asian population. This study evaluated the predictive ability of the CVAI for incident hypertension in Korean adults. METHODS: The study participants included 128,577 Koreans without hypertension. They were grouped in quartiles according to body mass index (BMI), waist circumference (WC), visceral adipose index (VAI), and CVAI values. The Cox proportional hazard assumption was used to evaluate the hazard ratio (HR) and 95% confidence interval (CI) for incident hypertension (adjusted HR [95% CI]) according to quartile level across a follow-up period of 6.9 years. Subgroup analyses were conducted by gender and obesity. The area under the curve was calculated to compare the predictive abilities of all indices (BMI, WC, VAI, and CVAI) for incident hypertension. RESULTS: The CVAI was proportionally associated with the risk of hypertension in all participants (quartile 1: reference; quartile 2: 1.71 [95% CI, 1.59 to 1.82]; quartile 3: 2.41 [95% CI, 2.25 to 2.58]; and quartile 4: 3.46 [95% CI, 3.23 to 3.71]). Time dependent receiver operating characteristic curve analysis indicated that the CVAI was superior to BMI, WC, and VAI in predicting hypertension at the 2-year, 4-year, 6-year, and 8-year follow-ups. This finding was also observed in the gender and obesity subgroups. The predictive ability of the CVAI was greater in the women and non-obese subgroups than in the men and obese subgroups. CONCLUSIONS: The CVAI was a stronger predictor of hypertension than BMI, WC, and VAI.

Integrated "-omics" analysis highlights the role of brassinosteroid signaling and antioxidant machinery underlying improved rice seed longevity during artificial aging treatment.

Seed longevity is a critical characteristic in agriculture, yet the specific genes/proteins responsible for this trait and the molecular mechanisms underlying reduced longevity during seed aging remain largely elusive. Here we report the comparative proteome and metabolome profiling of three rice cultivars exhibiting varying degrees of aging tolerance: Dharial, an aging-tolerant cultivar; Ilmi, an aging-sensitive cultivar; and A2, a moderately aging-tolerant cultivar developed from the crossbreeding of Dharial and Ilmi. Artificial aging treatment (AAT) markedly reduced the germination percentage and enhanced the activities of antioxidant enzymes in all the cultivars. Further, proteomics results showed a key role of the ubiquitin (Ub)-proteasome pathway in the degradation of damaged proteins during AAT while other proteases were majorly reduced. In addition, proteins associated with energy production and protein synthesis were strongly reduced in Ilmi while these were majorly increased in A2 and Dharial. These, along with metabolomics results, suggest that Ub-proteasome mediated protein degradation during AAT results in the accumulation of free amino acids in Ilmi while tolerant cultivars potentially utilize those for energy production and synthesis of stress-related proteins, especially hsp20/alpha-crystallin family protein. Additionally, both Dharial and A2 seem to activate brassinosteroid signaling and suppress jasmonate signaling which initiates a signaling cascade that allows accumulation of enzymatic and non-enzymatic antioxidants for efficient detoxification of aging-induced ROS. Taken together, these results provide an in-depth understanding of the aging-induced changes in rice seeds and highlight key pathways responsible for maintaining seed longevity during AAT.

Association Between Eight Autoimmune Diseases and Thyroid Cancer: A Nationwide Cohort Study.

Background: It has often been reported that thyroid-specific autoimmune diseases (ADs), such as Hashimoto's thyroiditis and Graves' disease, could increase the risk of thyroid cancer, but the association between other ADs beyond thyroid and thyroid cancer has not been well investigated. This study aimed to examine the risk of thyroid cancer in patients with eight ADs compared with those without ADs. Methods: This nationwide retrospective matched cohort study was conducted to investigate the relationship of eight ADs (Hashimoto's thyroiditis, Graves' disease, type 1 diabetes mellitus, Sjogren's disease, inflammatory bowel disease [IBD], vitiligo, systemic lupus erythematosus, and rheumatoid arthritis [RA]) with the risk of incident thyroid cancer using the National Health Insurance Service-National Sample Cohort. The Cox-proportional hazard model was used to estimate the adjusted hazard ratio (HR) and confidence intervals (CI) for thyroid cancer in relation to each of AD compared with control group without AD. Results: During the average follow-up of 9.49 years, 138 thyroid cancer cases were newly developed in control group and 268 cases were occurred in group with 8 ADs. For all of study participants, the risk of thyroid cancer was significantly increased in patients with Hashimoto's thyroiditis (HR = 2.10 [1.57-2.81]), Graves' disease (HR = 2.67 [1.99-3.62]), IBD (HR = 2.06 [1.50-2.83]), vitiligo (HR = 1.71 [1.13-2.59]), RA (HR = 1.76 [1.07-2.90]), and total of 8 ADs (HR = 1.97 [1.60-2.42]) compared with control group without ADs. When ADs were divided into three types, thyroid-specific ADs (HR = 2.37 [1.85-3.03]) showed the strongest and significant association with thyroid cancer, followed by local ADs (HR = 1.83 [1.41-2.38]), and systemic ADs (HR = 1.77 [1.14-2.74]). Conclusions: Specific ADs-especially for thyroid-specific AD, vitiligo, IBD, and RA-were associated with increased risk for thyroid cancer.

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.

Neuroprotective Effects of Water Extract from Brown Algae Petalonia binghamiae in an Experimental Model of Focal Cerebral Ischemia In Vitro and In Vivo.

Focal cerebral ischemia (fCI) can result in brain injury and sensorimotor deficits. Brown algae are currently garnering scientific attention as potential therapeutic candidates for fCI. This study investigated the therapeutic effects of the hot water extract of Petalonia binghamiae (wPB), a brown alga, in in vitro and in vivo models of fCI. The neuroprotective efficacy of wPB was evaluated in an in vitro excitotoxicity model established using HT-22 cells challenged with glutamate. Afterward, C57/BL6 mice were administered wPB for 7 days (10 or 100 mg/kg, intragastric) and subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) operation, which was used as an in vivo fCI model. wPB co-incubation significantly inhibited cell death, oxidative stress, and apoptosis, as well as stimulated the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, and the nuclear translocation of its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-22 cells challenged with glutamate-induced excitotoxicity. Pretreatment with either dose of wPB significantly attenuated infarction volume, neuronal death, and sensorimotor deficits in an in vivo fCI model. Furthermore, the attenuation of oxidative stress and apoptosis in the ischemic lesion accompanied the wPB-associated protection. This study suggests that wPB can counteract fCI via an antioxidative effect, upregulating the Nrf2/HO-1 pathway.

Changes in proteinuria and the associated risks of ischemic heart disease, acute myocardial infarction, and angina pectoris in Korean population.

OBJECTIVES: Proteinuria is widely used to predict cardiovascular risk. However, there is insufficient evidence to predict how changes in proteinuria may affect the incidence of cardiovascular disease. METHODS: The study included 265,236 Korean adults who underwent health checkups in 2003-2004 and 2007-2008. They were categorized into 4 groups based on changes in proteinuria (negative: negative → negative; resolved: proteinuria ≥1+ → negative; incident: negative → proteinuria ≥1+; persistent: proteinuria ≥1+ → proteinuria ≥1+). We conducted 6 years of follow-up to identify the risks of developing ischemic heart disease (IHD), acute myocardial infarction (AMI), and angina pectoris according to changes in proteinuria. A multivariate Cox proportional-hazards model was used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident IHD, AMI, and angina pectoris. RESULTS: The IHD risk (expressed as HR [95% CI]) was the highest for persistent proteinuria, followed in descending order by incident and resolved proteinuria, compared with negative proteinuria (negative: reference, resolved: 1.211 [95% CI, 1.104 to 1.329], incident: 1.288 [95% CI, 1.184 to 1.400], and persistent: 1.578 [95% CI, 1.324 to 1.881]). The same pattern was associated with AMI (negative: reference, resolved: 1.401 [95% CI, 1.048 to 1.872], incident: 1.606 [95% CI, 1.268 to 2.035], and persistent: 2.069 [95% CI, 1.281 to 3.342]) and angina pectoris (negative: reference, resolved: 1.184 [95% CI, 1.065 to 1.316], incident: 1.275 [95% CI, 1.160 to 1.401], and persistent: 1.554 [95% CI, 1.272 to 1.899]). CONCLUSIONS: Experiencing proteinuria increased the risks of IHD, AMI, and angina pectoris even after proteinuria resolved.

Changes in smoking status, amount of smoking and their relation to the risk of microvascular complications in men with diabetes mellitus.

BACKGROUND: Smoking is a definite risk factor for macrovascular complications in diabetes mellitus (DM). However, the effect of smoking on microvascular complications is inconclusive. METHOD: Study participants were 26,673 diabetic men who received health check-up both in 2003-2004 and 2009, excluding women. Assessing smoking status (never, quitting and current) at 2003-2004 and 2009, changes in smoking status were categorised into 7 groups (never - never, never - quitting, never - current, quitting-quitting, quitting-current, current-quitting and current-current). Smoking amount was categorised into never, light (0-10 pack years), moderate (10-20 pack years), and heavy smoking (>20 pack years) based on 2009 data. They were followed-up until 2013 to identify incident microvascular complications. We calculated the adjusted hazard ratios (HR) and 95% confidence interval (CI) (adjusted HR [95% CI]) for incident microvascular complications according to changes in smoking status and smoking amount. RESULTS: Current-quitting (1.271 [1.050-1.538]), current-current (1.243 [1.070-1.444]) and heavy smoking (1.238 [1.078-1.422]) were associated with an increased risk of overall microvascular complications. The risk of nephropathy increased in current-current smoking (1.429 [1.098-1.860]) and heavy smoking (1.357 [1.061-1.734]). An increased risk of neuropathy was observed in current-quitting smoking (1.360 [1.076-1.719]), current-current smoking (1.237 [1.025-1.492]) and heavy smoking (1.246 [1.048-1.481]). However, we couldn't see the interpretable findings for the association between smoking and retinopathy. CONCLUSIONS: Lasting and heavy smoking increases the risk of microvascular complications, including nephropathy and neuropathy. Quitting smoking and reducing smoking amount are imperative in preventing microvascular complications in DM patients.

Comparative Proteome-wide Characterization of Three Different Tissues of High-Protein Mutant and Wild Type Unravels Protein Accumulation Mechanisms in Rice Seeds.

Improving the proteins and amino acid contents of rice seeds is one of the prime objectives of plant breeders. We recently developed an EMS mutant/high-protein mutant (HPM) of rice that exhibits 14.8% of the total protein content as compared to its parent Dharial (wild-type), which shows only 9.3% protein content in their mature seeds. However, the mechanisms underlying the higher protein accumulation in these HPM seeds remain largely elusive. Here, we utilized high-throughput proteomics to examine the differences in the proteome profiles of the embryo, endosperm, and bran tissues of Dharial and HPM seeds. Utilizing a label-free quantitative proteomic and subsequent functional analyses of the identified proteins revealed that nitrogen compound biosynthesis, intracellular transport, protein/amino acid synthesis, and photosynthesis-related proteins were specifically enriched in the endosperm and bran of the high-protein mutant seed. Our data have uncovered proteome-wide changes highlighting various functions of metabolic pathways associated with protein accumulation in rice seeds.

Longitudinal analysis for the risk of depression according to the consumption of sugar-sweetened carbonated beverage in non-diabetic and diabetic population.

Studies have presented that high intake of sugar-sweetened carbonated beverage (SSCB) was more associated with the prevalence of depression. However, longitudinal evidence is still insufficient to identify whether the effect of SSCB on incident depression is independent of metabolic factors. Therefore, to evaluate the effect of SSCB consumption on the risk of depression, we analyzed the risk of depression according to the consumption of SSCB in 87,115 working aged Koreans who responded to Center for Epidemiologic Studies Depression (CES-D) scale. They were categorized into 5 groups by SSCB consumption based on one serving dose (200 ml) with never/almost never, < 1 serving/week, 1 ≤ serving/week < 3, 3 ≤ serving/week < 5, and 5 ≤ serving/week. During follow-up, CES-D ≥ 16 was determined as incident depressive symptom. Cox proportional hazards model was used to calculate the multivariable-adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptom. In analysis for all study participants, the risk of depressive symptom significantly increased proportionally to SSCB consumption (never/almost never: reference, < 1 serving/week: 1.12 [1.07-1.17], 1 ≤ ~ < 3 serving/week: 1.26 [1.19-1.33], 3 ≤ ~ < 5 serving/week: 1.32 [1.23-1.42], and ≥ 5 serving/week: 1.45 [1.33-1.59]). This association was identically observed in men, women, normal glycemic subgroup and prediabetes subgroup.

Dietary sodium intake and its relation to sleep duration, sleep quality and nocturnal urination in working-aged Korean adults.

Both sodium intake and sleep have an important effect on cardiovascular health. However, few studies have looked at the association between sodium intake and sleep. Therefore, we analysed the association of sodium intake with sleep quality, sleep duration and nocturnal urination. The data for the present study were obtained from the Kangbuk Samsung Health Study. Study participants were 156 696 working-aged Korean adults (average age 38.0 years ±8.0 in men and 36.0 years ±8.1 in women). They were categorised into five groups by quintile of sodium intake, measured by food frequency questionnaire. Poor sleep quality and short sleep duration were determined by Pittsburgh Sleep Quality Index >5, and sleep duration <7 h, respectively. Nocturnal urination was defined as awakening to urinate more than three times a week. Multivariable adjusted logistic regression analysis was used in calculating the odds ratio (OR) and 95% confidence interval (CI) for poor sleep quality, short sleep duration and nocturnal urination (adjusted OR [95% CI]) across five study groups. In all study participants, increased sodium intake was significantly associated with poor sleep quality (quintile 1: reference, quintile 2: 1.07 [1.04-1.11], quintile 3: 1.12 [1.08-1.16], quintile 4: 1.15 [1.11-1.19] and quintile 5: 1.13 [1.09-1.18]). This pattern of relationship was similarly observed in association of sodium intake with short sleep duration (p for trend <0.001) and nocturnal urination (p for trend <0.001). In gender subgroup analysis, increased sodium intake had a significant association with poor sleep quality and short sleep duration in men and with poor sleep quality and nocturnal urination in women. In conclusion, high sodium intake is associated with an increased likelihood of poor sleep quality, short sleep duration and nocturnal urination.

Proteome profiling highlights mechanisms underlying pigment and tocopherol accumulation in red and black rice seeds.

Rice is a major component of the human diet and feeds more than 50 million people across the globe. We previously developed two pigmented rice cultivars, Super-hongmi (red seeds) and Super-jami (black seeds), that are highly rich in antioxidants and exhibit high levels of radical scavenging activities. However, the molecular mechanism underlying the accumulation of pigments and different antioxidants in these rice cultivars remains largely elusive. Here, we report the proteome profiles of mature Super-hongmi and Super-jami seeds, and compared them with the Hopum (white seeds) using a label-free quantitative proteomics approach. This approach led to the identification of 5127 rice seed proteins of which 1628 showed significant changes in the pigmented rice cultivar(s). The list of significantly modulated proteins included a phytoene desaturase (PDS3) which suggested accumulation of ζ-carotene in red seeds while the black seeds seem to accumulate more of anthocyanins because of the higher abundance of dihydroflavonol 4-reductase. Moreover, proteins associated with lignin and tocopherol biosynthesis were highly increased in both red and black cultivars. Taken together, these data report the seed proteome of three different colored rice seeds and identify novel components associated with pigment accumulation in rice.

Proteomic Analysis Reveals a Critical Role of the Glycosyl Hydrolase 17 Protein in Panax ginseng Leaves under Salt Stress.

Ginseng, an important crop in East Asia, exhibits multiple medicinal and nutritional benefits because of the presence of ginsenosides. On the other hand, the ginseng yield is severely affected by abiotic stressors, particularly salinity, which reduces yield and quality. Therefore, efforts are needed to improve the ginseng yield during salinity stress, but salinity stress-induced changes in ginseng are poorly understood, particularly at the proteome-wide level. In this study, we report the comparative proteome profiles of ginseng leaves at four different time points (mock, 24, 72, and 96 h) using a label-free quantitative proteome approach. Of the 2484 proteins identified, 468 were salt-responsive. In particular, glycosyl hydrolase 17 (PgGH17), catalase-peroxidase 2, voltage-gated potassium channel subunit beta-2, fructose-1,6-bisphosphatase class 1, and chlorophyll a-b binding protein accumulated in ginseng leaves in response to salt stress. The heterologous expression of PgGH17 in Arabidopsis thaliana improved the salt tolerance of transgenic lines without compromising plant growth. Overall, this study uncovers the salt-induced changes in ginseng leaves at the proteome level and highlights the critical role of PgGH17 in salt stress tolerance in ginseng.

The protective effect of mushroom consumption on depressive symptoms in Korean population.

Mushrooms are nutraceutical food with health benefit. However, available data is still limited in identifying the effect of mushrooms consumption on depressive symptoms. In a cohort of 87,822 Korean, we longitudinally assessed the risk of depressive symptoms according to mushrooms consumption. Study participants were categorized into 5 groups by the frequency of one serving size of mushrooms (30 g) as follows: rare/never, < 1/month, 1/month-1/week, 1-3/week, ≥ 3/week. The development of depressive symptoms was determined in Center for epidemiological studies-depression scale ≥ 16. Cox proportional hazards model was used to calculate adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptoms (adjusted HR [95% CI]). Subgroup analysis was performed for gender and age. Compared with group with rare/never consumption, groups with mushrooms consumption ≥ one serving size/month had the significantly decreased levels in adjusted HR and 95% CI for depressive symptoms (rare/never consumption: reference, < 1/month: 0.92 [0.83-1.02], 1/month-1/week: 0.88 [0.83-0.94], 1-3/week: 0.88 [0.82-0.94], ≥ 3/week: 0.86 [0.80-0.93]). This association was similarly observed in both gender and age subgroup analyses. However, women and participants ≥ age of 40 showed the more prominent association than men and participants < age of 40.

Fasting blood glucose and risk of incident pancreatic cancer.

BACKGROUND: The number of patients with diabetes and impaired fasting blood glucose in Korea is rapidly increasing compared to the past, and other metabolic indicators of population are also changed in recent years. To clarify the mechanism more clearly, we investigated the association between fasting blood glucose and incidence of pancreatic cancer in this retrospective cohort study. METHODS: In Korea National Health Information Database, 19,050 participants without pancreatic cancer in 2009 were enrolled, and followed up until 2013. We assessed the risk of incident pancreatic cancer according to the quartile groups of fasting blood glucose level (quartile 1: <88 mg/dL, quartile 2: 88-97 mg/dL, quartile 3: 97-109 mg/dL and quartile 4: ≥109 mg/dL). Multivariate Cox-proportional hazard model was used in calculating hazard ratios (HRs) and 95% confidence interval (CI) for incident pancreatic cancer. RESULTS: Compared with quartile1 (reference), unadjusted HRs and 95% CI for incident pancreatic cancer significantly increased in order of quartile2 (1.39 [1.01-1.92]), quartile3 (1.50 [1.09-2.07]) and quartile4 (2.18 [1.62-2.95]), and fully adjusted HRs and 95% CI significantly increased from quartile2 (1.47 [1.05-2.04]), quartile3 (1.61 [1.05-2.04]) to quartile4 (2.31 [1.68-3.17]). CONCLUSION: Fasting blood glucose even with pre-diabetic range was significantly associated with the incident pancreatic cancer in Korean.

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.

The association between changes in proteinuria and the risk of cerebral infarction in the Korean population.

BACKGROUND: Proteinuria is a risk factor for cerebral infarction. It is known that proteinuria can change over time. However, published data is scarce for the association between changes in proteinuria and the risk of cerebral infarction. METHOD: Study participants were 276,861 Koreans who were assessed for urine dipstick proteinuria both in 2003-2004 and 2007-2008. They were categorized into four groups by changes in proteinuria over 4 years (negative: negative â†’ negative, resolved: proteinuria ≥ 1+ → negative, incident: negative â†’ proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1 + ). We used multivariate adjusted Cox-proportional hazard model in calculating the adjusted hazard ratios (HR) and 95% confidence interval (CI) for cerebral infarction until 2013 according to changes in proteinuria. RESULT: Adjusted HR and 95% CI for cerebral infarction significantly increased in order of persistent, incident, and resolved proteinuria, compared with negative proteinuria (negative: reference, resolved: 1.166 [1.009-1.347], incident: 1.345 [1.188-1.522], and persistent: 1.443 [1.089-1.912]). In gender subgroup analysis, men showed the more clear association between changes in proteinuria and the risk of cerebral infarction (negative: reference, resolved: 1.284 [1.057-1.560], incident: 1.351 [1.149-1.589], and persistent: 1.428 [1.014-2.012]). CONCLUSION: All types of proteinuria changes were associated with the increased risk of cerebral infarction, even in participants with once manifested but vanishing proteinuria.

Nationwide changes in physical activity, nutrient intake, and obesity in South Korea during the COVID-19 pandemic era.

Background: This study aimed to examine changes in obesity rates and obesity-related factors during the COVID-19 pandemic compared to a previous period. Methods: An ecological time-series study was designed using the Korean National Health and Nutritional Examination Survey (KNHANES) database from 2014 to 2020. The expected values of obesity rate, physical activity rate, and nutrient intake for 2020 were estimated. The differences between the predicted and actual values for 2020 were also examined. In addition, a multiple logistic regression model was used to examine the changes in obesity and physical activity rates in 2020 compared to 2019. Results: The actual obesity rates in 2020 were higher, and the walking and aerobic physical activity rates were lower than the predicted values for the same year. However, the actual resistance training rates in 2020 were higher and the total energy intake was lower than the predicted values for 2020. In the multiple logistic regression model, the odds ratios for obesity, aerobic physical activity, and walking among men in 2020 were 1.29 (95% CI: 1.08 to 1.55), 0.86 (0.74 to 1.01), and 0.84 (0.73 to 0.97), respectively, compared to those in 2019. However, there were no significant differences between the values for women in 2020 and 2019. Conclusions: This study suggests that the male obesity rate in Korea has significantly increased during the COVID-19 epidemic, mainly due to a decrease in physical activity.

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.