Anti-neuroinflammatory Effects of Active Compound SPA1413 via Suppression of the MAPK and JAK/STAT Signaling Pathways.

Isoflavones and their derivatives possess neuroprotective activities against neurological disorders. Recently, the active compound SPA1413 (dehydroequol) derived from S-equol, an isoflavone-derived metabolite produced by human intestinal bacteria, was identified as a potent anti-amyloidogenic and neuroinflammatory candidate against Alzheimer's disease. However, its detailed modes of action, associated signaling pathways, and comparison with potential isoflavone derivatives have not yet been studied. Hence, the current study aimed to identify signaling pathways associated with SPA1413 using lipopolysaccharides (LPS)-stimulated BV2 cells as the experimental model via biological assays, Western blotting, and quantitative (q)RT-PCR. The results indicate that the SPA1413 anti-neuroinflammatory effect arises due to suppression of the nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and mitogen-activated protein kinase (MAPK) signaling networks, including those of p38 and c-Jun N-terminal kinase (JNK). Interestingly, SPA1413 inhibited IL-11 through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. In addition, SPA1413 inhibited neuronal cell death by reducing LPS-activated microglia in neuronal N2a cells. Our findings suggest that SPA1413 may act as a strong anti-neuroinflammatory candidate by suppressing the MAPK and JAK/STAT signaling pathways.

Neurotrophic phenolic glycosides from the roots of Armoracia rusticana.

Armoracia rusticana P. G. Gaertner. belongs to the Brassicaceae family and has aroused scientific interest for its anti-inflammatory and anticancer activities. In a continuing investigation to discover bioactive constituents from A. rusticana, we isolated 19 phenolic glycosides including three undescribed flavonol glycosides and one undescribed neolignan glycoside from MeOH extract of this plant. Their structures were elucidated based on NMR spectroscopic analysis (1H, 13C, 1H-1H COSY, HSQC, and HMBC), HRESIMS, and chemical methods. The determination of their absolute configuration was accomplished by ECD and LC-MS analysis. All the compounds were assessed for their potential neurotrophic activity through induction of nerve growth factor in C6 glioma cell lines and for their anti-neuroinflammatory activity based on the measurement of inhibition levels of nitric oxide production and pro-inflammatory cytokines (i.e., IL-1ß, IL-6, and TNF-α) in lipopolysaccharide-activated microglia BV-2 cells.

Triterpenoids from the leaves of Abies koreana and their biological activities.

Seven undescribed triterpenoids, abikoranes A-G, along with three known triterpenoids were isolated from the leaves of Abies koreana E. H. Wilson. The structures of compounds were elucidated by 1D and 2D NMR, HRMS, ECD, specific rotation, and DP4+ analysis. Abikorane A represents the second example of nor-3,4-seco-17,14-friedo-lanostane triterpenoid. Among the isolates, some compounds showed strong cytotoxic activities against some of four tested cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-116) with the values of IC50 0.89-9.62 µM, inhibited lipopolysaccharide-stimulated nitric oxide production with IC50 values of 11.57-15.16 µM, and exhibited significant nerve growth factor release effect (192.54 ± 12.33%) from C6 glioma cells.

Total Synthesis of Isohericerinol A and Its Analogues to Access Their Potential Neurotrophic Effects.

The secondary metabolites from Hericium erinaceus are well-known to have neurotrophic and neuroprotective effects. Isohericerinol A (1), isolated by our colleagues from its fruiting parts has a strong ability to increase the nerve growth factor secretion in C6 glioma cells. The current work describes the total synthesis of 1 and its regioisomer 5 in a few steps. We present two different approaches to 1 and a regiodivergent approach for both 1 and 5 by utilizing easily accessible feedstocks. Interestingly, the natural product 1, regioisomer 5, and their intermediates exhibited potent neurotrophic activity in in vitro experimental systems. Thus, these synthetic strategies provide access to a systematic structure-activity relationship study of natural product 1.

18p Deletion Syndrome Originating from Rare Unbalanced Whole-Arm Translocation between Chromosomes 13 and 18: A Case Report and Literature Review.

18p deletion (18p-) syndrome is a rare chromosome abnormality that has a wide range of phenotypes, with short stature, intellectual disability, and facial dysmorphism being the main clinical features. Here, we report the first case in Korea of a 16-year-old male adolescent with 18p- syndrome resulting from de novo unbalanced whole-arm translocation between chromosomes 13 and 18 (45, XY, der(13;18)(q10:q10)). Three rare clinical findings were discovered that had not been reported in the previous literature; morbid obesity without other hormonal disturbances, rib cage deformity leading to the direct compression of the liver, and lumbar spondylolisthesis at the L5-S1 level. This case expands the phenotypic spectrum of 18p- syndrome and highlights the importance of considering chromosomal analysis, since this syndrome can be easily overlooked in a clinical setting, especially without distinctive symptoms of other organs, due to its nonspecific but typical features of short stature and mild intellectual disability with a mildly dysmorphic face. Moreover, since not all cases of 18p- syndrome with unbalanced translocation (13;18) show the same phenotype, multidisciplinary examinations and follow-up seem to be important to monitor evolving and developing clinical manifestations and to predict prognosis in advance associated with the specific genes of 18p breakpoint regions.

Changes in the Epidemiology and Causative Pathogens of Meningitis in Children After the Outbreak of the Coronavirus Disease 2019: A Multicenter Database Study.

Background: With the outbreak of the COVID-19 pandemic, non-pharmaceutical interventions such as social distancing have been implemented worldwide, and a decrease in other infectious diseases has been reported as an unexpected benefit. However, to date, studies are lacking regarding the effects of the COVID-19 pandemic on neuroinfectious diseases; therefore, we aimed to determine the effects of the COVID-19 pandemic on the incidence of meningitis, which is the most common infectious disease in children. Methods: This retrospective study used electronic medical record data from five university hospitals located in the metropolitan cities in Korea. This study included patients aged <18 years who were diagnosed with meningitis between January 2017 and December 2020. We analyzed the clinical characteristics of patients with meningitis and changes in the incidence and causative pathogens of meningitis before and after the COVID-19 outbreak. Results: The study included 677 patients with meningitis. Following the outbreak of COVID-19 in Korea in January 2020, the incidence of childhood meningitis significantly decreased and seasonal changes noted yearly disappeared. There was a difference in the age distribution of patients with meningitis. The incidence of meningitis decreased significantly in children aged >5 years, and the incidence in children <5 years of age relatively increased (p < 0.001). In addition, there was a notable decrease in the cases of suspected meningitis (p < 0.001). The incidence of enteroviral meningitis, the most common cause of meningitis, significantly decreased. Conclusion: After the COVID-19 outbreak, the incidence of childhood meningitis significantly decreased with the implementation of non-pharmaceutical interventions. Absence of enteroviral meningitis and decrease in the proportion of patients aged ≥5 years with meningitis having mild symptoms were noted. Consequently, it can be concluded that the non-pharmaceutical interventions (NPIs) instituted to prevent the spread of COVID-19 had some effect on reducing the incidence of meningitis.

Procyanidins and Phlobatannins from the Twigs of Rosa multiflora and Their Neuroprotective Activity.

Three new procyanidins (1-3), two new phlobatannins (6 and 7), a new flavan-3,4-diol glycoside (9), and a new neolignan glycoside (10), along with three previously reported compounds (4, 5, and 8) were isolated from the twigs of Rosa multiflora. The chemical structures of the new compounds (1-3, 6, 7, 9, and 10) were characterized by spectroscopic data interpretation, including NMR (1H and 13C NMR, 1H-1H COSY, HSQC, HMBC, and NOESY) and HRESIMS analysis. Experimental ECD data analysis was conducted to assign the absolute configurations of the new compounds (1-3, 6, 7, 9, and 10). The absolute configuration of the sugar moieties was verified through a chiral derivatization method and LC-MS analysis. All the isolated compounds (1-10) were evaluated for their anti-neuroinflammatory activity based on inhibitory effects on nitric oxide production using a lipopolysaccharide-stimulated murine microglia BV-2 cell line and for their neurotrophic effects on nerve growth factor induction in C6 glioma.

TAZ promotes PDX1-mediated insulinogenesis.

Transcriptional co-activator with PDZ-binding motif (TAZ) is a key mediator of the Hippo signaling pathway and regulates structural and functional homeostasis in various tissues. TAZ activation is associated with the development of pancreatic cancer in humans, but it is unclear whether TAZ directly affects the structure and function of the pancreas. So we sought to identify the TAZ function in the normal pancreas. TAZ defect caused structural changes in the pancreas, particularly islet cell shrinkage and decreased insulin production and ß-cell markers expression, leading to hyperglycemia. Interestingly, TAZ physically interacted with the pancreatic and duodenal homeobox 1 (PDX1), a key insulin transcription factor, through the N-terminal domain of TAZ and the homeodomain of PDX1. TAZ deficiency decreased the DNA-binding and transcriptional activity of PDX1, whereas TAZ overexpression promoted PDX1 activity and increased insulin production even in a low glucose environment. Indeed, high glucose increased insulin production by turning off the Hippo pathway and inducing TAZ activation in pancreatic ß-cells. Ectopic TAZ overexpression along with PDX1 activation was sufficient to produce insulin in non-ß-cells. TAZ deficiency impaired the mesenchymal stem cell differentiation into insulin-producing cells (IPCs), whereas TAZ recovery restored normal IPCs differentiation. Compared to WT control, body weight increased in TAZ-deficient mice with age and even more with a high-fat diet (HFD). TAZ deficiency significantly exacerbated HFD-induced glucose intolerance and insulin resistance. Therefore, TAZ deficiency impaired pancreatic insulin production, causing hyperglycemia and exacerbating HFD-induced insulin resistance, indicating that TAZ may have a beneficial effect in treating insulin deficiency in diabetes.

A Mixture of Ginkgo biloba L. Leaf and Hericium erinaceus (Bull.) Pers. Fruit Extract Attenuates Scopolamine-Induced Memory Impairments in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by loss of memory and cognitive impairment via dysfunction of the cholinergic nervous system. In cholinergic dysfunction, it is well known that impaired cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling are major pathological markers and are some of the strategies for the development of AD therapy. Therefore, this study is aimed at evaluating whether a mixture comprising Ginkgo biloba L. leaf (GL) and Hericium erinaceus (Bull.) Pers. (HE) fruit extract (GH mixture) alleviated cognitive impairment induced in a scopolamine-induced model. It was discovered that GH reduced neuronal apoptosis and promoted neuronal survival by activating BDNF signaling in an in vitro assay. In addition, the GH (p.o. 240 mg/kg) oral administration group significantly restored the cognitive deficits of the scopolamine-induced mouse group (i.p. 1.2 mg/kg) in the behavior tests such as Y-maze and novel object recognition task (NORT) tests. This mixture also considerably enhanced cholinergic system function in the mouse brain. Furthermore, GH markedly upregulated the expressed levels of extracellular signal-regulated kinase (ERK), CREB, and BDNF protein levels. These results demonstrated that GH strongly exerted a neuroprotective effect on the scopolamine-induced mouse model, suggesting that an optimized mixture of GL and HE could be used as a good material for developing functional foods to aid in the prevention of neurodegenerative diseases, including AD.

Phenolic constituents from twigs of Aleurites fordii and their biological activities.

Three new neolignan glycosides (1-3), a new phenolic glycoside (15), and a new cyanoglycoside (16) were isolated and characterized from the twigs of Aleurites fordii together with 14 known analogues (4-14 and 17-19). The structural elucidation of the new compounds was performed through the analysis of their NMR, HRMS, and ECD spectra and by chemical methods. All isolated compounds were tested for their antineuroinflammatory and neuroprotective activities.

Liver abscess due to Klebsiella pneumoniae in a healthy 12-year-old boy.

Pyogenic liver abscess (PLA) is rare in healthy children. We report a case of PLA in an immunocompetent 12-year-old boy. Percutaneous catheter drainage was performed for the abscess. In addition, parenteral antibiotics were administered for 3 weeks. Klebsiella pneumoniae was detected in the culture of blood and drained fluid. Here, we present this case and a brief review of the literature on this subject.