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Scope: Polymethoxylated flavones (PMFs) are a group of natural compounds known to display a wide array of beneficial effects to promote physiological fitness. Recent studies reveal circadian clocks as an important cellular mechanism mediating preventive efficacy of the major PMF Nobiletin against metabolic disorders. Sudachitin is a PMF enriched in Citrus sudachi, and its functions and mechanism of action are poorly understood., Methods and Results: Using circadian reporter cells, it shows that Sudachitin modulates circadian amplitude and period of Bmal1 promoter-driven reporter rhythms, and real-time qPCR analysis shows that Sudachitin alters expression of core clock genes, notably Bmal1, at both transcript and protein levels. Mass-spec analysis reveals systemic exposure in vivo. In mice fed with high-fat diet with or without Sudachitin, it observes increased nighttime activity and daytime sleep, accompanied by significant metabolic improvements in a circadian time-dependent manner, including respiratory quotient, blood lipid and glucose profiles, and liver physiology. Focusing on liver, RNA-sequencing and metabolomic analyses reveal prevalent diurnal alteration in both gene expression and metabolite accumulation., Conclusion: This study elucidates Sudachitin as a new clock-modulating PMF with beneficial effects to improve diurnal metabolic homeostasis and liver physiology, suggesting the circadian clock as a fundamental mechanism to safeguard physiological well-being., (© 2023 Wiley-VCH GmbH.)

In vitro and animal studies have indicated that extracts from the peel of the Japanese Citrus sudachi , including sudachitin, ameliorate hyperlipidemia and reduce obesity. Sudachitin, a polymethoxylated flavone, has been reported as having favorable effects on lipid and glucose metabolism but results from clinical trials have been inconsistent. The aim of this study was to determine the effect of consuming capsules of sudachi peel extract powder on visceral fat in Japanese men and women in a randomized controlled trial. This was a 12-week randomized, double-blind, placebo-controlled trial involving 41 participants aged 30-65 years with BMI 23-30 kg/m 2 , randomly allocated to receive either sudachi peel extract powder (sudachitin 4.9 mg/day, n  = 21) or placebo ( n  = 20) of identical appearance. The primary outcome measure was visceral fat mass, assessed during intervention. Thirty-eight of the 41 subjects completed the protocol. Compared with placebo, sudachi peel extract powder significantly reduced the ratio of visceral fat to subcutaneous fat, and moderately reduced waist circumference, a metabolic syndrome marker. Glycemic control and lipid profile were not changed significantly in these subjects. Consumption of capsules of sudachi peel extract powder favorably improves the ratio of visceral fat to subcutaneous fat in individuals at risk for developing diabetes, especially in individuals with large visceral fat area, while not adversely affecting glycemic control., Competing Interests: All supplements used in this study were provided by Ikeda Yakusou., (© 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Kawasaki disease (KD) is a childhood-onset vascular disease. In order to determine whether KD is associated with altered chemokine production, we measured CCL2, CCL22, and CXCL10 levels in the serum of KD patients and healthy control subjects. The mean serum concentration of CCL2 in KD subjects was 829.0 +/- 388.2 pg/ml, significantly higher than that seen in healthy controls (223.4 +/- 92.6 pg/ml; p < 0.001). In addition, the mean serum CXCL10 level in KD subjects was 2,469.4 +/- 998.8 pg/ml, again significantly higher than that in healthy controls (127.7 +/- 64.2 pg/ml; p < 0.001). No difference was observed in serum concentrations of CCL22 between KD and healthy controls (1,685 +/- 1,985 microg/ml and 1,539 +/- 380 microg/ml, respectively). Thus, we observed the selective induction of a TH1-associated (CXCL10) and a TH2-associated chemokine (CCL2) in the serum of individuals with KD, suggesting a mixed TH1/TH2 response at the level of chemokine production and subsequent cell recruitment and thus pointing at a potential role for these chemokines in the pathology of KD.

To define better the molecular basis for follicular dendritic cell (FDC) function, we used PCR-based cDNA subtraction to identify genes specifically expressed in primary FDC isolated from human tonsils. In this work we report the discovery of a novel gene encoding a small secreted protein, which we term FDC-SP (FDC secreted protein). The FDC-SP gene lies on chromosome 4q13 adjacent to clusters of proline-rich salivary peptides and C-X-C chemokines. Human and mouse FDC-SP proteins are structurally unique and contain a conserved N-terminal charged region adjacent to the leader peptide. FDC-SP has a very restricted tissue distribution and is expressed by activated FDCs from tonsils and TNF-alpha-activated FDC-like cell lines, but not by B cell lines, primary germinal center B cells, or anti-CD40 plus IL-4-activated B cells. Strikingly, FDC-SP is highly expressed in germinal center light zone, a pattern consistent with expression by FDC. In addition, FDC-SP is expressed in leukocyte-infiltrated tonsil crypts and by LPS- or Staphylococcus aureus Cowan strain 1-activated leukocytes, suggesting that FDC-SP can also be produced in response to innate immunity signals. We provide evidence that FDC-SP is posttranslationally modified and secreted and can bind to the surface of B lymphoma cells, but not T lymphoma cells, consistent with a function as a secreted mediator acting upon B cells. Furthermore, we find that binding of FDC-SP to primary human B cells is markedly enhanced upon activation with the T-dependent activation signals such as anti-CD40 plus IL-4. Together our data identify FDC-SP as a unique secreted peptide with a distinctive expression pattern within the immune system and the ability to specifically bind to activated B cells.

The n-hexane and ethyl acetate extracts of the stems and the ethyl acetate extracts of roots from Prangos pabularia afforded an gamma-pyrone derivative and furanocoumarin derivatives with three glucose and gamma-pyrone (pabularin A, B and C), along with 26 previously known compounds (18 coumarins, six terpenoids and two glycosides). Their structures were established on the basis of spectroscopic studies. Of these, 16 coumarin derivatives isolated from P. pabularia were tested for antibacterial activity and inhibition of cytokine release.

The methanol extract of the dried aerial parts of Prangos tschimganica gave three new coumarin derivatives and 30 known coumarin derivatives. Their structures were established on the basis of chemical and spectroscopic evidence. Absolute configuration of the isolated compounds were determined by using a modified Mosher's method. Some of the isolated compounds showed anti-HIV activity.

Kawasaki disease (KD) is a childhood-onset vascular disease. We assessed the concentrations of macrophage-colony stimulating factor (M-CSF) and those of lipids in sera from patients with KD. The M-CSF concentration in patients with acute-phase KD was 2,914+/-159 U/ml, significantly higher than that in control subjects with Infectious diseases (1,241+/-96 U/ml). The elevated levels of this cytokine in the acute phase fell to 1,319+/-138 U/ml in the convalescent phase. Total and high-density lipoprotein cholesterol concentrations in acute phase KD (113.8+/-8.4 and 21.5+/-2.3 mg/dl, respectively) were lower than in the infectious disease controls (195.8+/-7.0 and 62.5+/-1.8 mg/dl). The elevation of M-CSF correlated with the decrease of total and high-density lipoprotein cholesterol. Overproduction of macrophage-colony stimulating factor activates macrophages and monocytes and may disturb the lipid metabolism. Both effects could contribute to vasculitis in KD.

The methanol extract of the dried roots of Rheum maximowiczii afforded four phenylbutanoid and two stilbene derivatives. Their structures were established on the basis of chemical and spectroscopic studies.

The effects of roxithromycin, a macrolide antibiotic, on neutrophil activities were investigated in six seriously handicapped patients with severe mental retardation. Neutrophil activities were evaluated by flow cytometry using a heparinized blood analysis method. All six patients showed decreased levels of neutrophil phagocytosis, intracellular killing, and CD11b expression. Treatment with roxithromycin in vitro selectively restored the decreased phagocytic and bactericidal activities of neutrophils in these patients. There was no significant restorative effect with cefaclor, ofloxacin, or aztreonam. These results suggest the need to consider therapeutic effects of antibiotics on neutrophil functions in patients at increased risk for bacterial infections due to decreased neutrophil activities.

Effect of TYB-2285 and its metabolites on immune responses by peripheral blood mononuclear cells (PBMC) from children with bronchial asthma was investigated. TYB-2285 and its metabolites have immunosuppressive activity for the proliferation by Df-stimulated patients' lymphocytes. Concanavalin A (Con A)-activated peripheral blood mononuclear cells (PBMC) from the patients were not affected by the same treatment. The results indicate that TYB-2285 and its metabolites are capable of suppressing antigen-induced 3H-thymidine (3H-TdR) uptake but not the response induced by Con A. Interferon-gamma (IFN-gamma) production by Df-stimulated PBMC from patients with active asthma, which was lower than that of normal lymphocytes, were reversed beyond the levels of that in normal subjects. Thus reduced production of IFN-gamma by Df-stimulated patients' lymphocytes was increased by TYB-2285 and its metabolites in a dose-dependent manner. This phenomenon was not observed in lymphocytes from normal subjects. Furthermore, TYB-2285 inhibited IL-4 production induced by Df antigen in asthmatic patients' lymphocytes. Taken, together, TYB-2285 could work as a weak immunosuppressant to modify lymphocytes' responses to allergen in patients with bronchial asthma. These data underscore the potential benefit for the patients with bronchial asthma.