Construction of intermolecular σ-hole interactions in rare earth metallocene complexes using a 2,3,4,5-tetraiodopyrrolyl anion.

The generation of noncovalent intermolecular interactions represents a powerful method to control molecular vibrations and rotations. Combining these with the axial ligand field enforced by the metallocene ligand scaffold provides a dual-pronged approach in controlling the magnetic-relaxation pathways for dysprosium-based single-molecule magnets (SMMs). Here, we present the first implementation of 2,3,4,5-tetraiodopyrrole (TIPH) in its anionic form [TIP]- as a ligand in three isostructural rare-earth metal complexes Cp*2RE(TIP) (1-RE, RE = Y, Gd, and Dy; Cp* = pentamethylcylopentadienyl), where the TIP ligand binds through the nitrogen and one iodine atom κ2(N,I) to the metal centre. The shallow potential energy surface of the intermolecular σ-hole interaction yields distortions of the interatomic distances at elevated temperatures which were investigated by variable-temperature SCXRD. 1-RE constitute the first crystallographically characterized molecules containing TIP as a ligand for any metal ion, and 1-Dy is the first SMM that employs the TIP ligand. The structural dependence on temperature allowed the mechanism of magnetic relaxation to be explored through ab initio calculations at different temperatures. The electronic influence of the coordinated iodine substituent was probed via magnetometry and cw-EPR spectroscopy on 1-Gd. To further scrutinize the impact of the iodine substituents on the physical properties, a second set of new complexes Cp*2RE(DMP) (2-RE, RE = Y, and Dy) where DMP = 2,5-dimethylpyrrolyl were synthesized. Here, the DMP ligand binds similarly to the TIP ligand and represents an all-hydrocarbon analogue to 1-RE. 2-Dy constitutes the first SMM bearing a DMP ligand.

Anti-Metastatic Effects of Standardized Polysaccharide Fraction from Diospyros kaki Leaves via GSK3ß/ß-Catenin and JNK Inactivation in Human Colon Cancer Cells.

A polysaccharide fraction from Diospyros kaki (PLE0) leaves was previously reported to possess immunostimulatory, anti-osteoporotic, and TGF-ß1-induced epithelial-mesenchymal transition inhibitory activities. Although a few beneficial effects against colon cancer metastasis have been reported, we aimed to investigate the anti-metastatic activity of PLE0 and its underlying molecular mechanisms in HT-29 and HCT-116 human colon cancer cells. We conducted a wound-healing assay, invasion assay, qRT-PCR analysis, western blot analysis, gelatin zymography, luciferase assay, and small interfering RNA gene silencing in colon cancer cells. PLE0 concentration-dependently inhibited metastasis by suppressing cell migration and invasion. The suppression of N-cadherin and vimentin expression as well as upregulation of E-cadherin through the reduction of p-GSK3ß and ß-catenin levels resulted in the outcome of this effect. PLE0 also suppressed the expression and enzymatic activity of matrix metalloproteinases (MMP)-2 and MMP-9, while simultaneously increasing the protein and mRNA levels of the tissue inhibitor of metalloproteinases (TIMP-1). Furthermore, signaling data disclosed that PLE0 suppressed the transcriptional activity and phosphorylation of p65 (a subunit of NF-κB), as well as the phosphorylation of c-Jun and c-Fos (subunits of AP-1) pathway. PLE0 markedly suppressed JNK phosphorylation, and JNK knockdown significantly restored PLE0-regulated MMP-2/-9 and TIMP-1 expression. Collectively, our data indicate that PLE0 exerts an anti-metastatic effect in human colon cancer cells by inhibiting epithelial-mesenchymal transition and MMP-2/9 via downregulation of GSK3ß/ß-catenin and JNK signaling.

SYNGAP1-related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights.

The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole-exome sequencing. All patients exhibited global developmental delay from early infancy, with motor development eventually reaching independent ambulation by 3 years of age. Language developmental delay varied significantly from nonverbal to simple sentences, which plateaued in all patients. Patients with the best language outcomes typically managed 2-3-word sentences, corresponding to a developmental age of 2-3 years. Epilepsy developed in 77% of patients, with onset consistently following developmental delays at a median age of 31 months. Longitudinal EEG data revealed a shift from occipital to frontal epileptiform discharges with age, suggesting a correlation with synaptic maturation. These findings suggest that the critical developmental plateau occurs between the ages of 2 and 5 years and is potentially influenced by epilepsy. By analyzing longitudinal data, our study contributes to a deeper understanding of SYNGAP1-related DEE, provides potential EEG biomarkers, and underlines the importance of early diagnosis and intervention to address this complex disorder.

Protective effect of hydrangenol on lipopolysaccharide-induced endotoxemia by suppressing intestinal inflammation.

Hydrangenol, a dihydroisocoumarin, isolated from the leaves of Hydrangea serrata, possesses anti-inflammatory, anti-obesity, and anti-photoaging activities. In this study, we investigated the protective effects of hydrangenol (HG) against lipopolysaccharide (LPS)-induced endotoxemia and elucidated the underlying molecular mechanisms of action in C57BL/6 mice. Oral administration of HG (20 or 40 mg/kg) significantly restored the survival rate and population of macrophages, T helper cells (CD3+/CD4+), and Th17 cells (CD3+/CD4+/CCR6+) in the spleens of mice with LPS-induced endotoxemia. HG suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, and Interferon (IFN)-γ and the mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in the intestine and lung of LPS-treated mice. Molecular data showed that HG ameliorated the activation of nuclear factor kappa B (NF-κB) p65, signal transducers and activators of transcription 3 (STAT3), and c-Fos and c-Jun (AP-1 subunits) via the myeloid differentiation primary response 88 (MyD88) dependent toll-like receptor 4 (TLR4) signaling pathway in the LPS-treated mouse intestines. HG treatment caused the recovery of LPS-induced impaired tight junction (occludin and claudin-2) protein and mRNA expressions. Furthermore, HG improved LPS-induced gut dysbiosis in mice. Taken together, our results suggest that HG protects against LPS-induced endotoxemia by restoring immune cells and the capacity of the intestinal barrier, reducing intestinal inflammation, and improving the composition of the gut microbiota.

Pyrrolyl-Bridged Metallocene Complexes: From Synthesis, Electronic Structure, to Single-Molecule Magnetism.

The π- and σ-basicity of the pyrrolyl ligand affords several coordination modes. A sterically encumbering coordination sphere around metal centers may foster new coordination modes for the pyrrolyl ligand. Here, we present three dinuclear rare earth complexes [Cp*2RE(µ-pyr)]2, [RE = Y (1), La (2), Dy (3); Cp* = pentamethylcyclopentadienyl, pyr = pyrrolyl], which were synthesized through a protonolysis reaction between allyl complexes and H-pyrrole. Each metal is ligated by two Cp* ligands and the N atom of the pyrrolyl ring while interacting with the π-system of the other pyrrolyl ligand, yielding an unprecedented coordination mode for pyrrolyl best described as [((η5-Cp*)2RE)2(µ-1η2-pyr-2κN)(µ-2η2-pyr-1κN)]. The steric congestion implemented by the Cp* ligands forces this asymmetric coordination of the pyrrolyl ligand. 1-3 were characterized by crystallography, electrochemistry, and spectroscopy. Density functional theory calculations on 1 uncovered the bonding situation between the pyrrolyl ligand and the yttrium(III) ion. Excitingly, 3 displays slow magnetic relaxation under zero dc field with Ueff = 98.9(7) cm-1 and τo = 6.7(1) × 10-8 s, placing it among coveted dinuclear metallocene single-molecule magnets. CASSCF calculations provided the energy of the crystal field states of DyIII and confirmed the barrier height.

Hydrangenol, an active constituent of Hydrangea serrata (Thunb.) Ser., ameliorates colitis through suppression of macrophage-mediated inflammation in dextran sulfate sodium-treated mice.

Ulcerative colitis (UC) is a chronic disease of the colon characterized by mucosal damage and relapsing gastrointestinal inflammation. Hydrangea serrata (Thunb.) Ser. and its bioactive compound, hydrangenol, are reported to have anti-inflammatory effects, but few studies have investigated the effects of hydrangenol in colitis. In the present study, we evaluated for the first time the anti-colitic effects and molecular mechanisms of hydrangenol in a dextran sodium sulfate (DSS)-induced mouse colitis model. To investigate the anti-colitic effects of hydrangenol, DSS-induced colitis mice, HT-29 colonic epithelial cells treated with supernatant from LPS-inflamed THP-1 macrophages, and LPS-induced RAW264.7 macrophages were used. In addition, to clarify the molecular mechanisms of this study, quantitative real time-PCR, western blot analysis, TUNEL assay, and annexin V-FITC/PI double staining analysis were conducted. Oral administration of hydrangenol (15 or 30 mg kg-1) significantly alleviated DSS-induced colitis by preventing DAI scores, shortening colon length, and colonic structural damage. F4/80+ macrophage numbers in mesenteric lymph nodes and macrophage infiltration in colonic tissues were significantly suppressed following hydrangenol treatment in DSS-exposed mice. Hydrangenol significantly attenuated DSS-induced destruction of the colonic epithelial cell layer through regulation of pro-caspase-3, occludin, and claudin-1 protein expression. Moreover, hydrangenol ameliorated abnormal tight junction protein expression and apoptosis in HT-29 colonic epithelial cells treated with supernatant from LPS-inflamed THP-1 macrophages. Hydrangenol suppressed the expression of pro-inflammatory mediators, such as iNOS, COX-2, TNF-α, IL-6, and IL-1ß through NF-κB, AP-1, and STAT1/3 inactivation in DSS-induced colon tissue and LPS-induced RAW264.7 macrophages. Taken together, our findings suggest that hydrangenol recovers the tight junction proteins and down-regulates the expression of the pro-inflammatory mediators by interfering with the macrophage infiltration in DSS-induced colitis. Our study provides compelling evidence that hydrangenol may be a candidate for inflammatory bowel disease therapy.

Design, synthesis, and evaluation of new anti-inflammatory natural products amide derivatives endowed with anti-blood cancer activity towards development of potential multifunctional agents against hematological cancers.

New amide derivatives of the natural product 5,6,7-trimethoxyflavanone were designed as multifunctional antiproliferative molecules against blood cancer and the associated inflammatory conditions. The targeted compounds were synthesized efficiently in three linear steps employing known chalcone starting materials. Compounds 2h, 2i, 2l, 2t, 2v and 2x having bromo or nitro substituted-phenyl rings elicited potential inhibitory effects on macrophages production of nitric oxide, PGE2 and TNF-α which are proinflammatory mediators involved in tumorigenesis and progression of blood cancer. Additionally, evaluation of direct inhibitory effects on the growth of diverse blood cancers including leukemia, lymphoma, and myeloma cell lines unveiled compound 2v as the most potential molecules eliciting at least five-folds the potency of the standard imatinib drug over the used diverse blood cancers. Furthermore, compound 2v showed good selectivity to blood cancer cells rather than normal MRC5 cells. Moreover, compound 2v triggered death of HL60 leukemia cells via apoptosis induction. In conclusion, the natural product-derived compound 2v might serve as a multifunctional lead compound for further development of agents for treatment of blood cancers.

Anti-Leukemic Effects of Idesia polycarpa Maxim Branch on Human B-Cell Acute Lymphoblastic Leukemia Cells.

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL.

Antinociceptive and anti-inflammatory activity of DW-1021, the ionic complex of pelubiprofen and tramadol, in rodents.

Although drugs such as acetaminophen, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used for pain management, the side effects of these drugs such as hepatotoxicity, nephrotoxicity, nausea, and vomiting, can not be neglected. Therefore, combinations of analgesics with different mechanisms raise the possibility of developing novel analgesics. Therefore, the aim of the present study was to evaluate whether DW-1021, the ionic complex of pelubiprofen (NSAID) and tramadol (opioid), has synergic antinociceptive and anti-inflammatory effects in nociceptive as well as inflammation-induced nociceptive models compared to pelubiprofen- or tramadol-only administration. Strong synergistic antinociceptive efficacy of DW-1021 was observed in the mouse writhing test and von Frey paw withdrawal threshold test in the carrageenan-induced rats. The hot plate test in mice and the Randall-Selitto mechanical paw pressure test in carrageenan-induced rats revealed that DW-1021 had a preferable effect on relieving pain to pelubiprofen, but not as much as tramadol. In the carrageenan-induced rats, DW-1021 had a more potent effect on reducing paw inflammation (paw volume, width, and thickness) via the suppression of PGE2 production than tramadol, but less than that of pelubiprofen. Taken together, our results suggest that the administration of DW-1021, a combination of pelubiprofen and tramadol, exerted a potent effect and can be used as a potential therapeutic agent for relieving pain and inflammation.

A case of pediatric anti-leucine-rich glioma inactivated 1 encephalitis with faciobrachial dystonic seizure.

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a rare type of autoimmune encephalitis. A characteristic faciobrachial dystonic seizure (FBDS) is also frequently associated with this disease. Although primarily reported in the adult population, reports of its occurrence in the pediatric population are rare. Here, we describe a case of a 6-year-old girl diagnosed with anti-LGI1 encephalitis that presented with cognitive decline and FBDS. CASE PRESENTATION: The girl was referred to a pediatric neurology department for uncontrolled seizures and dyskinesia. She initially presented with a memory deficit, abnormal movement of the limbs and trunk, and ataxia. Her cerebrospinal fluid exam was unremarkable, but her brain MRI showed focal T2 high signal intensity in the left anterior putamen and right caudate nucleus. In addition, there were refractory episodes of brief tonic or dystonic movement of the face and arms that were suggestive of FBDS. She was initially treated with intravenous methylprednisolone and phenobarbital, then given another pulse of methylprednisolone and intravenous immunoglobulin as her symptoms persisted. Tests for neuronal autoantibodies revealed the presence of anti-LGI1 antibodies. Subsequent human leukocyte antigen (HLA) typing resulted in the identification of HLA-DRB1 DR7(*07:01 g) DR9(*09:01 g). Screening for thymoma and other neoplasms showed no signs of a tumor. She was treated with rituximab, tocilizumab, and antiseizure medications, including oxcarbazepine, valproic acid, and lamotrigine. Her FBDS and cognitive symptoms showed substantial improvements. CONCLUSION: While it is known that anti-LGI1 encephalitis responds well to immunotherapy, our patient showed an incomplete response, requiring further therapy. This is the first report of a pediatric patient with anti-LGI1 encephalitis treated with tocilizumab.

Association of blood pressure and hypertension between parents and offspring: The Korea National Health and Nutrition Examination Survey.

As the number of hypertension cases in the pediatric population is growing, we aimed to investigate the parent-offspring association of hypertension in Korea. We performed a cross-sectional analysis using the data of children and adolescents aged 10-18 years and their parents extracted from the Korea National Health and Nutrition Examination Survey (2008-2018). We analyzed the correlation of blood pressure (BP) between offspring and their parents and investigated the odds ratio (OR) of having hypertension in offspring based on parental hypertensive status. A total of 3996 children and adolescents (2224 boys and 1772 girls) aged 10-18 years and their parents (3197 fathers and 3197 mothers) were evaluated. Both boys and girls had positive associations with both parents for systolic and diastolic BP. When neither parent, only the father, only the mother, or both parents were hypertensive, 6.6%, 10.4%, 13.3%, and 25.3% of boys and 6%, 12%, 12.7%, and 22.1% of girls had hypertension, respectively. The risk of having hypertension among offspring was approximately two times higher when one parent was hypertensive and over four times higher when both parents were hypertensive compared to that among controls whose parents were not hypertensive (OR: 2.230, 1.655, and 5.021 in boys with hypertension and 2.321, 2.169, and 4.554 in girls with hypertension in the mother only, the father only, and both parents, respectively). We identified familial aggregation of hypertension in Korea. As there was an increased likelihood of having hypertension in children with parental hypertension, parental hypertension may be utilized as a screening tool for hypertension in children.

Dieckol Isolated from Eisenia bicyclis Ameliorates Wrinkling and Improves Skin Hydration via MAPK/AP-1 and TGF-ß/Smad Signaling Pathways in UVB-Irradiated Hairless Mice.

Repetitive exposure to ultraviolet B (UVB) is one of the main causes of skin photoaging. We previously reported that dieckol isolated from Eisenia bicyclis extract has potential anti-photoaging effects in UVB-irradiated Hs68 cells. Here, we aimed to evaluate the anti-photoaging activity of dieckol in a UVB-irradiated hairless mouse model. In this study, hairless mice were exposed to UVB for eight weeks. At the same time, dieckol at two doses (5 or 10 mg/kg) was administered orally three times a week. We found that dieckol suppressed UVB-induced collagen degradation and matrix metalloproteinases (MMPs)-1, -3, and -9 expression by regulating transforming growth factor beta (TGF-ß)/Smad2/3 and mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) signaling. In addition, dieckol rescued the production of hyaluronic acid (HA) and effectively restored the mRNA expression of hyaluronan synthase (HAS)-1/-2 and hyaluronidase (HYAL)-1/-2 in UVB-irradiated hairless mice. We observed a significant reduction in transepidermal water loss (TEWL), epidermal/dermal thickness, and wrinkle formation in hairless mice administered dieckol. Based on these results, we suggest that dieckol, due to its anti-photoaging role, may be used as a nutricosmetic ingredient for improving skin health.

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome.

Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the LMNA (MIM 150330) gene. APS has heterogeneous clinical manifestations, and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy. He had been treated for recurrent urinary tract infection during infancy, and liver biopsy for persisting hepatitis showed steatohepatitis. He also had hypertrophic cardiomyopathy (HCMP) with mitral and tricuspid valve regurgitation. Genetic studies were performed considering his multisystem symptoms, and he was diagnosed as having APS according to exome sequencing findings (c.898G > C, p.Asp300His of LMNA). During the first visit to the nephrology clinic, he had minimal proteinuria (urine protein/creatinine ratio of 0.23 mg/mg), which worsened during follow-up. In three years, his urine protein/creatinine ratio and N-acetyl-b-D-glucosaminidase/creatinine ratio increased to 1.52 and 18.7, respectively. The kidney biopsy result was consistent with findings of FSGS, peri-hilar type, showing segmental sclerosis of 1 (5%) glomerulus out of 21 glomeruli. An angiotensin receptor blocker was added to manage his proteinuria. This is the first pediatric report of FSGS in an APS patient with confirmed LMNA defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis. Our case suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.

A first nation-wide assessment of soil-transmitted helminthiasis in Fijian primary schools, and factors associated with the infection, using a lymphatic filariasis transmission assessment survey as surveillance platform.

BACKGROUND: Soil-transmitted helminthiasis (STH) is endemic in Fiji but its prevalence is not known and likely to have changed after a decade of mass drug administration (MDA) for lymphatic filariasis (LF). By linking with LF transmission assessment surveys (LF-TAS), we undertook the first nation-wide assessment of STH in Fijian primary schools, as well as an analysis of factors associated with STH infections. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional assessment for STH was conducted in all four Divisions of Fiji from 2014 to 2015. In the Western, Central, and Northern Divisions, schools were sub-sampled after LF-TAS, while, in the Eastern Division, schools were selected via simple random sampling. For the diagnosis of STH, stool samples were examined by coproscopy with a single Kato-Katz thick smear (KK) and the formol-ether-acetate concentration technique, except for the samples from the Eastern Division where only KK was used. Mean prevalence of any STH among class 1-2 students at the national level was 10.5% (95% CI: 6.9-15.5). Across the three Divisions via LF-TAS, the prevalence levels for ascariasis were 8.7% (95% CI: 4.3-16.6), hookworm 3.9% (95% CI: 2.3-6.6) and trichuriasis 0%. In the Eastern Division, ascariasis prevalence was 13.3% (95% CI: 6.4-25.6), and hookworm 0.7% (95% CI: 0.2-2.5), with one case of trichuriasis. Among class 3-8 students, ascariasis prevalence was lower. Lower risk of any STH was associated with wearing shoes (adjusted OR 0.54, 95% CI: 0.32-0.90) and having piped water from the Fiji Water Authority at home (adjusted OR 0.48, 95% CI: 0.25-0.92). CONCLUSIONS: After a decade of community-based LF-MDA, STH in school-age children in Fiji is now close to 10%, but localities of endemicity remain. Preventive chemotherapy should be maintained in areas with elevated STH prevalence alongside targeted delivery of integrated WASH interventions. LF-TAS has provided an opportunity to develop future public health surveillance platforms.