The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta.

BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aß/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aß/tau fibrillation, Aß plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100ß and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aß/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Traceless Nucleophile Strategy for C5-Selective C-H Sulfonylation of Pyridines.

The functionalization of pyridines is crucial for the rapid construction and derivatization of agrochemicals, pharmaceuticals, and materials. Conventional functionalization approaches have primarily focused on the ortho- and para-positions, while achieving precise meta-selective functionalization, particularly at the C5 position in substituted pyridines, remains a formidable challenge due to the intrinsic electronic properties of pyridines. Herein, we present a new strategy for meta- and C5-selective C-H sulfonylation of N-amidopyridinium salts, which employs a transient enamine-type intermediate generated through a nucleophilic addition to N-amidopyridinium salts. This process harnesses the power of electron donor-acceptor complexes, enabling high selectivity and broad applicability, including the construction of complex pyridines bearing valuable sulfonyl functionalities under mild conditions without the need for an external photocatalyst. The remarkable C5 selectivity, combined with the broad applicability to late-stage functionalization, significantly expands the toolbox for pyridine functionalization, unlocking access to previously unattainable meta-sulfonylated pyridines.

Lessons for Future Vaccination Policies: COVID-19 Vaccination Intention in People with and without Chronic Diseases.

PURPOSE: This study compared COVID-19 vaccination intentions in those with and without chronic diseases (CDs and non-CDs) in South Korea. We hypothesized that the factors associated with COVID-19 vaccination intentions would differ between CDs and non-CDs in South Korea. METHOD: Using survey data collected through a Korean online panel in June 2021, we conducted a cross-sectional secondary data analysis. Of the 2,292 participants, 411 had at least one chronic disease. To construct a comparable dataset, we selected non-CDs via a 1:1 case-control matching for age and gender. We then utilized a multivariable binary logistic regression model to explore the factors contributing to COVID-19 vaccination intentions in CDs and non-CDs. RESULTS: All told, 75% of participants in both groups indicated that they intended to vaccinate against COVID-19. In both groups, those who mistrusted general vaccine benefits reported significantly lower COVID-19 vaccination intentions. Regarding factors associated with vaccination intentions, CDs identified anxiety regarding coronavirus and exposure to COVID-19 vaccination promotions at the community level, while non-CDs highlighted hesitancy regarding vaccines and confidence in government/health services. CONCLUSION: Improving vaccination acceptance will require the development and implementation of tailored approaches for CDs and non-CDs and efforts to minimize general vaccine mistrust.

Gestodene, a novel positive allosteric modulator of PAR1, enhances PAR1-mediated human platelet aggregation.

Background: Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In this study, we discovered a novel PAM of PAR1 and investigated the effect of enhanced PAR1 activation by PAM of PAR1 on platelet activation. Methods: To find PAMs of PAR1, a cell-based screen was performed in HT29 cells, and finally, gestodene, an oral contraceptive drug (OC), was identified as a novel PAM of PAR1. The mechanism of action of gestodene and its effects on platelet activation were investigated in human megakaryocytic leukemia cell line MEG-01 cells and human platelet. Results: Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP induced morphological changes in MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1. Conclusion: Gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

Comparative analysis on natural variants of fire blight resistance protein FB_MR5 indicates distinct effector recognition mechanisms.

FB_MR5 is a nucleotide-binding domain and leucine-rich repeat protein identified from wild apple species Malus × robusta 5 conferring disease resistance to bacterial fire blight. FB_MR5 (hereafter MrMR5) recognizes the cysteine protease effector EaAvrRpt2 secreted from the causal agent of bacterial fire blight, Erwinia amylovora. We previously reported that MrMR5 is activated by the C-terminal cleavage product (ACP3) of Malus domestica RIN4 (MdRIN4) produced by EaAvrRpt2-directed proteolysis. We show that MbMR5 from a wild apple species Malus baccata shares 99.4% amino acid sequence identity with MrMR5. Surprisingly, transient expression of MbMR5 in Nicotiana benthamiana showed autoactivity in contrast to MrMR5. Domain swap and mutational analyses revealed that 1 amino acid polymorphism in the MbMR5 CC domain is critical in enhancing autoactivity. We further demonstrated that MrMR5 carrying 7 amino acid polymorphisms present in MbMR5 is not activated by MdRIN4 ACP3 but recognizes AvrRpt2 without MdRIN4 in N. benthamiana. Our findings indicate that naturally occurring polymorphisms of MR5 natural variants can confer its cell death-inducing activity and the effector recognition mechanism likely due to altered compatibility with RIN4.

Repurposing of the analgesic Neurotropin for MASLD/MASH treatment.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent decades. Approximately 25% of patients with MASLD progress to metabolic dysfunction-associated steatohepatitis, which is characterized by hepatic steatosis plus hepatocyte damage, inflammation, and fibrosis. We previously reported that Neurotropin (NTP), a drug used for relieving pain in Japan and China, inhibits lipid accumulation in hepatocytes by preventing mitochondrial dysfunction. We hypothesized that inhibiting hepatic steatosis and inflammation by NTP can be an effective strategy for treating MASLD and tested this hypothesis in a MASLD mouse model. METHODS: Six-week-old C57BL/6NJ male mice were fed a normal diet and normal drinking water or a high-fat diet with high fructose/glucose water for 12 weeks. During the last 6 weeks, the mice were also given high-dose NTP, low-dose NTP, or control treatment. Histologic, biochemical, and functional tests were conducted. MitoPlex, a new proteomic platform, was used to measure mitochondrial proteins, as mitochondrial dysfunction was previously reported to be associated with MASLD progression. RESULTS: NTP inhibited the development of hepatic steatosis, injury, inflammation, and fibrosis induced by feeding a high-fat diet plus high fructose/glucose in drinking water. NTP also inhibited HSC activation. MitoPlex analysis revealed that NTP upregulated the expression of mitochondrial proteins related to oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial dynamics, and fatty acid transport. CONCLUSIONS: Our results indicate that NTP prevents the development of hepatic steatosis, injury, and inflammation by preserving mitochondrial function in the liver and inhibits liver fibrosis by suppressing HSC activation. Thus, repurposing NTP may be a beneficial option for treating MASLD/metabolic dysfunction-associated steatohepatitis.

A Marine Collagen-Based 3D Scaffold for In Vitro Modeling of Human Prostate Cancer Niche and Anti-Cancer Therapeutic Discovery.

Recently, the need to develop a robust three-dimensional (3D) cell culture system that serves as a valuable in vitro tumor model has been emphasized. This system should closely mimic the tumor growth behaviors observed in vivo and replicate the key elements and characteristics of human tumors for the effective discovery and development of anti-tumor therapeutics. Therefore, in this study, we developed an effective 3D in vitro model of human prostate cancer (PC) using a marine collagen-based biomimetic 3D scaffold. The model displayed distinctive molecular profiles and cellular properties compared with those of the 2D PC cell culture. This was evidenced by (1) increased cell proliferation, migration, invasion, colony formation, and chemoresistance; (2) upregulated expression of crucial multidrug-resistance- and cancer-stemness-related genes; (3) heightened expression of key molecules associated with malignant progressions, such as epithelial-mesenchymal transition transcription factors, Notch, matrix metalloproteinases, and pluripotency biomarkers; (4) robust enrichment of prostate cancer stem cells (CSCs); and (5) enhanced expression of integrins. These results suggest that our 3D in vitro PC model has the potential to serve as a research platform for studying PC and prostate CSC biology, as well as for screening novel therapies targeting PC and prostate CSCs.

Oxidative balance scores in Korean adults are associated with periodontitis.

BACKGROUND: The Oxidative Balance Score (OBS) is a comprehensive metric that assesses the state of a person's oxidative balance. This study aimed to investigate the relationship between the oxidative balance score and moderate and severe periodontitis in a representative sample of Korean adults. METHODS: Healthcare big data from the 7th Korea National Health and Nutrition Examination Survey (2016-2018) was used, and 16,489 adults aged ≥19 years were included. Multivariate logistic regression analysis was performed to investigate the effect of sex-specific oxidative balance scores on periodontitis. RESULTS: In comparison with participants with a lower oxidative balance score, those with a higher oxidative balance score had a lower incidence of moderate and severe periodontitis (p < 0.05). After adjusting for covariates, the oxidative balance score was negatively associated with moderate (odds ratio [OR] = 0.952; 95% confidence interval [CI]: 0.934-0.971) and severe (OR = 0.958; 95% CI: 0.931-0.986) periodontitis; however, the result was not significant for severe periodontitis in women's (OR = 0.975; 95% CI: 0.934-1.018). Our study showed a statistically significant association between OBS and moderate and severe periodontitis, the small effect size should be interpreted with caution. CONCLUSIONS: The oxidative balance score was associated with moderate and severe periodontitis in Korean adults. Therefore, managing this score may help reduce the risk of periodontitis.

Femoral artery occlusion induced vasculopathy following herpes zoster: a case report.

BACKGROUND: Reactivation of the varicella zoster virus (VZV) results in herpes zoster (HZ), which is a painful unilateral rash with a typical dermatomal distribution. HZ may be followed by postherpetic neuralgia (PHN), vasculopathy, myelopathy, retinal necrosis, and cerebellitis. Vasculopathy can cause ischemic stroke, aneurysms, arterial dissection, transient ischemic attack, and rarely, peripheral arterial disease (PAD). The possible mechanism is that the VZV travels to the arteries through the sensory ganglia, leading to inflammation and pathological vascular remodeling, which result in vasculopathy. CASE DESCRIPTION: Here, we describe a rare case of femoral artery occlusion induced vasculopathy 5 years after HZ. A 65-year-old woman visited our pain clinic with persistent pain following HZ that occurred 3 months earlier. She had several rash scars on the right thigh along with a continuous throbbing, shooting, and sharp pain. The patient was diagnosed with PHN and prescribed with medications that relieved the leg pain. The symptoms remained stationary for almost 5 years. She presented again with complaints of a paroxysmal tingling sensation in the right thigh and claudication due to increased pain, which had begun 6 months prior. She reported leg pain after walking for 10 minutes. Lumbar spine magnetic resonance imaging (MRI) revealed foraminal stenosis at the level of right L2, with no abnormality below L2. Subsequently, the patient was evaluated for vascular diseases. Lower extremity ultrasonography and computed tomography (CT) angiography revealed stenosis and thrombotic occlusions in the right superficial femoral and tibial arteries as well as the left middle femoral and tibial arteries. Surgical revascularization via percutaneous angioplasty was performed bilaterally. The leg pain was relieved after the procedure and the claudication improved. CONCLUSIONS: Peripheral artery occlusion is a rare phenomenon following HZ. In cases involving changes in HZ symptoms, further evaluation is required for potential vasculopathy.

A Mycobacterium bovis outbreak among exhibition animals at a zoo in the Republic of Korea: the first contact investigation of zoonotic tuberculosis.

BACKGROUND: Between July 2, 2021, and September 20, 2022, a Mycobacterium bovis outbreak occurred among exhibition animals at a zoo in the Republic of Korea. This study was conducted to assess the likelihood of M. bovis transmission to human contacts through a contact investigation and to implement preventive treatment for latent tuberculosis infection (LTBI). METHODS: In this descriptive study, the Korea Disease Control and Prevention Agency conducted a contact investigation, which included interviews, interferon-gamma release assay (IGRA) tests, and chest X-rays. Contacts underwent IGRA testing on 2 occasions: initial testing of 29 contacts (15 in the first cluster of infection and 14 in the second cluster) and follow-up testing of the 15 contacts in the first cluster. RESULTS: The study included 29 participants, 18 of whom were male (62.1%) and 11 female (37.9%). The mean participant age was 37.3 years (standard deviation, 9.6 years). In the initial IGRA tests, 6 of the 29 participants tested positive, indicating a prevalence of 20.7%. Following prolonged exposure, 1 additional positive case was detected in follow-up testing, raising the prevalence of LTBI to 24.1%. None of the contacts had active tuberculosis. Among the 7 individuals with positive results, 2 (28.6%) underwent treatment for LTBI. CONCLUSION: This study faced challenges in confirming the transmission of M. bovis infection from infected animals to humans in the Republic of Korea. Nevertheless, adopting a One Health approach necessitates the implementation of surveillance systems and infection control protocols, particularly for occupational groups at high risk of exposure.

Evaluation of the effects of temperature and centrifugation time on elimination of uncured resin from 3D-printed dental aligners.

The study investigated the effects of temperature and centrifugation time on the efficacy of removing uncured resin from 3D-printed clear aligners. Using a photo-polymerizable polyurethane resin (Tera Harz TC-85, Graphy Inc., Seoul, Korea), aligners were printed and subjected to cleaning processes using isopropyl alcohol (IPA) or centrifugation (g-force 27.95g) at room temperature (RT, 23 °C) and high temperature (HT, 55 °C) for 2, 4, and 6 min. The control group received no treatment (NT). Cleaning efficiency was assessed through rheological analysis, weight measurement, transparency evaluation, SEM imaging, 3D geometry evaluation, stress relaxation, and cell viability tests. Results showed increased temperature and longer centrifugation times significantly reduced aligner viscosity, weight (P < 0.05), and transmittance. IPA-cleaned aligners exhibited significantly lower transparency and rougher surfaces in SEM images. All groups met ISO biocompatibility standards in cytotoxicity tests. The NT group had higher root mean square (RMS) values, indicating greater deviation from the original design. Stress relaxation tests revealed over 95% recovery in all groups after 60 min. The findings suggest that a 2-min HT centrifugation process effectively removes uncured resin without significantly impacting the aligners' physical and optical properties, making it a clinically viable option.

A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer's Disease in a Real-World Setting.

Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445).

Chronic kidney disease in postmenopausal women is associated with tooth loss.

OBJECTIVE: Menopause is characterized by changes in reproductive hormone levels that can negatively affect bone. Chronic kidney disease (CKD) and tooth loss are also important and common health issues after menopause. This study aimed to evaluate the association between CKD and tooth loss in postmenopausal women. METHODS: The study evaluated 64,971 participants who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) from 2010-2018, including postmenopausal women, aged 40 to 79 years. Participants were divided into two groups based on the number of teeth in their dentition (≥20 and <20). MAIN OUTCOME MEASURES: The association between CKD and tooth loss was analyzed using multivariate logistic regression. Age, income, education, smoking, alcohol intake, body mass index, hypertension, diabetes, annual oral examination, toothbrushing, and the use of oral care products were considered. Subgroup analyses were further conducted according to age (40-65 yr and 66-79 yr). RESULTS: After adjusting for covariates, CKD and estimated glomerular filtration rate were significantly associated with having ≥20 teeth (PT20; CKD: odds ratio [OR] 1.41, 95% confidence interval [CI] 1.04-1.90; estimated glomerular filtration rate (10 mL/min/1.73 m 2 ): OR 0.90, 95% CI 0.86-0.94). Importantly, the association between CKD and PT20 was significant in postmenopausal women, aged 66 to 79 years (OR 1.45, 95% CI 1.05-2.01). CONCLUSIONS: In postmenopausal women, CKD and tooth loss may be associated. The association is significant in postmenopausal women, aged 66 to 79 years.

Fucosylation and galactosylation in N-glycans of bovine intestinal alkaline phosphatase and their role in its enzymatic activity.

Bovine intestinal alkaline phosphatase (biALP), a membrane-bound plasma metalloenzyme, maintains intestinal homeostasis, regulates duodenal surface pH, and protects against infections caused by pathogenic bacteria. The N-glycans of biALP regulate its enzymatic activity, protein folding, and thermostability, but their structures are not fully reported. In this study, the structures and quantities of the N-glycans of biALP were analyzed by liquid chromatography-electrospray ionization-high energy collision dissociation-tandem mass spectrometry. In total, 48 N-glycans were identified and quantified, comprising high-mannose [6 N-glycans, 33.1 % (sum of relative quantities of each N-glycan)], hybrid (6, 11.9 %), and complex (36, 55.0 %) structures [bi- (13, 26.1 %), tri- (16, 21.5 %), and tetra-antennary (7, 7.4 %)]. These included bisecting N-acetylglucosamine (33, 56.6 %), mono-to tri-fucosylation (32, 53.3 %), mono-to tri-α-galactosylation (16, 20.7 %), and mono-to tetra-ß-galactosylation (36, 58.5 %). No sialylation was identified. N-glycans with non-bisecting GlcNAc (9, 10.3 %), non-fucosylation (10, 13.6 %), non-α-galactosylation (26, 46.2 %), and non-ß-galactosylation (6, 8.4 %) were also identified. The activity (100 %) of biALP was reduced to 37.3 ± 0.2 % (by de-fucosylation), 32.7 ± 2.9 % (by de-α-galactosylation), and 0.2 ± 0.2 % (by de-ß-galactosylation), comparable to inhibition by 10-4 to 101 mM EDTA, a biALP inhibitor. These results indicate that fucosylated and galactosylated N-glycans, especially ß-galactosylation, affected the activity of biALP. This study is the first to identify 48 diverse N-glycan structures and quantities of bovine as well as human intestinal ALP and to demonstrate the importance of the role of fucosylation and galactosylation for maintaining the activity of biALP.

Anticancer Effect of Hemin through ANO1 Inhibition in Human Prostate Cancer Cells.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 µM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 µM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.

Efficacy Assessment of Five Policosanol Brands and Damage to Vital Organs in Hyperlipidemic Zebrafish by Six-Week Supplementation: Highlighting the Toxicity of Red Yeast Rice and Safety of Cuban Policosanol (Raydel®).

Policosanol is a mixture of long-chain aliphatic alcohols (LCAAs) derived from various plant and insect origins that are marketed by various companies with distinct formulations and brand names. Policosanols offer several beneficial effects to treat dyslipidemia and hypertension; however, a comprehensive functionality comparison of various policosanol brands has yet to be thoroughly explored. In the present study five distinct policosanol brands from different origins and countries, Raydel-policosanol, Australia (PCO1), Solgar-policosanol, USA (PCO2), NutrioneLife-monacosanol, South Korea (PCO3), Mothernest-policosanol, Australia (PCO4), and Peter & John-policosanol, New Zealand (PCO5) were compared via dietary supplementation (1% in diet, final wt/wt) to zebrafish for six weeks to investigate their impact on survivability, blood lipid profile, and functionality of vital organs under the influence of a high-cholesterol diet (HCD, final 4%, wt/wt). The results revealed that policosanol brands (PCO1-PCO5) had a substantial preventive effect against HCD-induced zebrafish body weight elevation and hyperlipidemia by alleviating total cholesterol (TC) and triglycerides (TG) in blood. Other than PCO3, all the brands significantly reduced the HCD's elevated low-density lipoprotein cholesterol (LDL-C). On the contrary, only PCO1 displayed a significant elevation in high-density lipoprotein cholesterol (HDL-C) level against the consumption of HCD. The divergent effect of PCO1-PCO5 against HCD-induced hepatic damage biomarkers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), was observed. PCO1, PCO2, and PCO4 efficiently curtailed the AST and ALT levels; however, PCO3 and PCO5 potentially aggravated the HCD's elevated plasma AST and ALT levels. Consistently, the hepatic histology outcome revealed the least effectiveness of PCO3 and PCO5 against HCD-induced liver damage. On the contrary, PCO1 exhibited a substantial hepatoprotective role by curtailing HCD-induced fatty liver changes, cellular senescent, reactive oxygen species (ROS), and interleukin-6 (IL-6) production. Likewise, the histological outcome from the kidney, testis, and ovary revealed the significant curative effect of PCO1 against the HCD-induced adverse effects. PCO2-PCO5 showed diverse and unequal results, with the least effective being PCO3, followed by PCO5 towards HCD-induced kidney, testis, and ovary damage. The multivariate interpretation based on principal component analysis (PCA) and hierarchical cluster analysis (HCA) validated the superiority of PCO1 over other policosanol brands against the clinical manifestation associated with HCD. Conclusively, different brands displayed distinct impacts against HCD-induced adverse effects, signifying the importance of policosanol formulation and the presence of aliphatic alcohols on the functionality of policosanol products.

Endometriosis presenting as a perianal abscess: case report.

Endometriosis is common benign disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. Endometriosis of perianal region is a rare condition. We report a case of perianal endometriosis presenting initially as a perianal abscess. Transperineal ultrasound showed a 1.5 cm size irregular mixed echogenicity lesion without involving anal sphincters. Complete surgical excision was performed. The histopathological examination confirmed as endometriosis.

Heterogeneous field response of hierarchical polar laminates in relaxor ferroelectrics.

Understanding the microscopic origin of the superior electromechanical response in relaxor ferroelectrics requires knowledge not only of the atomic-scale formation of polar nanodomains (PNDs) but also the rules governing the arrangements and stimulated response of PNDs over longer distances. Using x-ray coherent nanodiffraction, we show the staggered self-assembly of PNDs into unidirectional mesostructures that we refer to as polar laminates in the relaxor ferroelectric 0.68PbMg1/3Nb2/3O3-0.32PbTiO3 (PMN-0.32PT). We reveal the highly heterogeneous electric-field-driven responses of intra- and interlaminate PNDs and establish their correlation with the local strain and the nature of the PND walls. Our observations highlight the critical role of hierarchical lattice organizations on macroscopic material properties and provide guiding principles for the understanding and design of relaxors and a wide range of quantum and functional materials.

B-Cell Lymphoma Arising From a Nasal Implant: A Brief Clinical Study.

Continuous exposure to foreign substances initiates a sustained inflammatory reaction in the body, and subsequent chronic inflammation is recognized as one of the causes of lymphoma. Most lymphomas caused by foreign bodies are composed of 2 major phenotypes. Diffuse large B-cell lymphoma arising from metallic prosthesis, also called metallic implant-associated lymphoma and T-cell phenotype anaplastic large cell lymphoma, commonly associated with breast implants. Augmentation rhinoplasty is often performed to improve the esthetics of the nasal dorsum and various synthetic materials have been used as implants. The occurrence of lymphoma originating from a nasal implant is scarcely documented, and even more uncommon is its manifestation as epstein-barr virus (EBV)-negative extranodal marginal zone lymphoma. Here, the authors describe a rare case of B-cell lymphoma of the nose and nasolacrimal duct in a 49-year-old woman who underwent rhinoplasty with a silicone implant 20 years ago.