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Ampelopsis grossedentata (AG) is an ancient medicinal plant that is mainly distributed and used in southwest China. It exerts therapeutic effects, such as antioxidant, anti-diabetic, and anti-inflammatory activities, reductions in blood pressure and cholesterol and hepatoprotective effects. Researchers in China recently reported the anti-obesity effects of AG extract in diet-induced obese mice and rats. To verify these findings, we herein investigated the effects of AG extract and its principal compound, ampelopsin, in high-fat diet (HFD)- and alcohol diet-fed mice, olive oil-loaded mice, and differentiated 3T3-L1 cells. The results obtained showed that AG extract and ampelopsin significantly suppressed increases in the weights of body, livers and abdominal fat and also up-regulated the expression of carnitine palmitoyltransferase 1A in HFD-fed mice. In olive oil-loaded mice, AG extract and ampelopsin significantly attenuated increases in serum triglyceride (TG) levels. In differentiated 3T3-L1 cells, AG extract and ampelopsin promoted TG decomposition, which appeared to be attributed to the expression of hormone-sensitive lipase. In alcohol diet-fed mice, AG extract and ampelopsin reduced serum levels of ethanol, glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) and liver TG. An examination of metabolic enzyme expression patterns revealed that AG extract and ampelopsin mainly enhanced the expression of aldehyde dehydrogenase and suppressed that of cytochrome P450, family 2, subfamily e1. In conclusion, AG extract and ampelopsin suppressed diet-induced intestinal fat accumulation and reduced the risk of fatty liver associated with HFD and alcohol consumption.

Ceramide (Cer) plays an important role in skin barrier functions in the stratum corneum (SC). The ingestion of food-derived glucosylceramides (GlcCer) attenuates transepidermal water loss (TEWL). However, the moisturizing effects of single molecules of GlcCer and Cer remain unclear. Therefore, we herein purified 13 GlcCer and 6 Cer, including elasticamide, which has the same structure as human Cer[AP], from rice and compared their epidermal moisturizing effects in a reconstructed human epidermal keratinization model. The results obtained showed that 10 µM of 5 GlcCer[d18:2] with a 4E,8Z sphingadienine and C18 to C26 fatty acids and 10 µg/mL of 3 Cer with C23 or C24 fatty acids significantly reduced TEWL. The moisturizing effects of these GlcCer were dependent on the length of fatty acids. Furthermore, 10 µg/mL of elasticamide increased the SC Cer contents by promoting the expression of GlcCer synthase. Electron microscopic observations revealed that 1 µM of GlcCer[d18:2(4E,8Z)/26:0] increased the number of keratohyalin granules and desmosomes. Immunostaining and Western blotting indicated that 1 µM of GlcCer[d18:2(4E,8Z)/26:0] up-regulated the expression of filaggrin and corneodesmosin, which contribute to epidermal hydration. This comparative study on epidermal moisturization by GlcCer and Cer isolated from rice revealed differences in their hydration mechanisms.

Tomatoes are widely consumed, however, studies on tomato seeds are limited. In this study, we isolated 11 compounds including saponins and flavonol glycosides from tomato seeds and evaluated their effects on epidermal hydration. Among the isolated compounds, tomato seed saponins (10 µM) significantly increased the mRNA expression of proteins related to epidermal hydration, including filaggrin, involucrin, and enzymes for ceramide synthesis, by 1.32- to 1.91-fold compared with the control in HaCaT cells. Tomato seed saponins (10 µM) also decreased transepidermal water loss by 7 to 13 g/m2·h in the reconstructed human epidermal keratinization (RHEK) models. Quantitative analysis of the ceramide content in the stratum corneum (SC) revealed that lycoperoside H (1–10 µM) is a promising candidate to stimulate ceramide synthesis via the upregulation of ceramide synthase-3, glucosylceramide synthase, and β-glucocerebrosidase, which led to an increase in the total SC ceramides (approximately 1.5-fold) in concert with ceramide (NP) (approximately 2-fold) in the RHEK models. Evaluation of the anti-inflammatory and anti-allergic effects of lycoperoside H demonstrated that lycoperoside H is suggested to act as a partial agonist of the glucocorticoid receptor and exhibits anti-inflammatory effects (10 mg/kg in animal test). These findings indicate that lycoperoside H can improve epidermal dehydration and suppress inflammation by increasing SC ceramide and steroidal anti-inflammatory activity.

Mountain caviar is a fruit of Kochia scoparia that contains momordin Ic as a major saponin constituent. Its extract (MCE) has been shown to suppress blood glucose elevations in the human oral glucose tolerance test (OGTT) as well as increases in blood glucose in OGTT, gastric emptying (GE), and glucose incorporation in the small intestine in rats. However, the effects of MCE and momordin Ic on glucose absorption in mice and these action mechanisms have not been examined for more than 2 decades. Therefore, we herein investigated the effects of MCE, its saponin fraction, and momordin Ic on blood glucose elevations in mice. Mouse blood glucose elevation tests were performed on carbohydrate-loaded mice. The mountain caviar saponin fraction significantly delayed blood glucose elevations in glucose-, sucrose-, and soluble starch-loaded mice. In glucose-loaded mice, the saponin fraction, MCE, and momordin Ic significantly suppressed rapid glucose elevations after glucose loading, but not sucrose loading. A mouse GE study was performed by loading with glucose and phenolphthalein solution. Momordin Ic and MCE strongly suppressed mouse GE. Intestinal glucose absorption was evaluated by the incorporation of 2-deoxyglucose (2-DG) into Caco-2 cell layers and mouse duodenum wall vesicles. The results obtained showed that momordin Ic inhibited the incorporation of 2-DG into Caco-2 cells and mouse duodenum vesicles. Collectively, these results suggest that MCE, particularly the principal saponin, momordin Ic, preferably suppressed glucose-induced blood glucose elevations and delayed carbohydrate-induced glucose elevations in mice. The underlying mechanism was found to involve the suppression of GE and intestinal glucose absorption. Graphical Abstract

Strawberry guava is the fruit of Psidium littorale, which grows in tropical regions. Few studies have examined the hydrophobic compounds and biological activities of this fruit. Therefore, we purified lipophilic compounds of strawberry guava and examined their effects on epidermal and blood vessel barrier functions as well as their anti-melanogenic activity. Lipophilic compounds were isolated by silica gel column chromatography followed by reversed-phase HPLC with MeOH from an EtOH extract of the fruit. Isolated compounds were identified by comparing NMR and MS spectra with those of reference values. The effects of these compounds on epidermal barrier function were evaluated by measuring transepidermal water loss (TEWL) using reconstructed human epidermal keratinocytes (RHEKs). Blood vessel barrier function was examined using dye permeability through human umbilical vein endothelial cell (HUVEC) layers. Anti-melanogenic activity was assessed by theophylline-induced melanogenesis in B16 melanoma cells. We isolated six glucosylceramides (GlcCers) and three digalactosyldiacylglycerols (DGDGs). Only GlcCer[t18:1(8Z)/23:0] significantly lowered TEWL in RHEKs, while GlcCer[t18:1(8Z)/24:0] induced a slight reduction. Regarding the permeability of the HUVEC layer, GlcCer[d18:2(4E,8Z)/16:0] and DGDG (1,2-dilinolenoyl-3-digalactosylglycerol) significantly suppressed dye permeability and this effect was accompanied by the expression of VE-cadherin, which facilitates cell-to-cell adhesion. GlcCers and DGDGs did not exhibit anti-melanogenic activity. Therefore, strawberry guava containing specific GlcCers and DGDGs may promote epidermal and blood vessel barrier functions.

Objectives The aim was to investigate the long-term prophylactic efficacy, drug retention and safety of low-dose sulfamethoxazole–trimethoprim (SMX/TMP) prophylaxis against Pneumocystis pneumonia (PCP). Methods Adult patients with rheumatic diseases receiving prednisolone ≥0.6 mg/kg/day were randomized into the single-strength group (SS; SMX/TMP 400/80 mg daily), the half-strength group (HS; 200/40 mg daily) or the escalation group (ES; starting at 40/8 mg and increasing incrementally to 200/40 mg daily) and treated for 24 weeks, then observed for 52 weeks. The primary endpoint, the PCP non-incidence rate (non-IR) at week 24, has been reported previously. The secondary endpoints were the PCP non-IR at week 52, treatment discontinuation rate and adverse events. Results Fifty-eight, 59 and 55 patients in the SS, HS and ES, respectively, received SMX/TMP. PCP did not develop in any of the patients by week 52. The estimated PCP non-IR in patients receiving SMX/TMP 200/40 mg daily (HS and ES) was 96.8–100%. Throughout the 52-week observation period, the overall discontinuation rate was significantly lower in HS than in SS (22.7 vs 47.2%, P = 0.004). The discontinuation rates attributable to adverse events were significantly lower in HS (19.1%, P = 0.007) and ES (20.3%, P = 0.007) than in SS (41.8%). The IRs of adverse events requiring SMX/TMP dose reduction before week 52 differed among the three groups, with a significantly higher IR in SS than in HS or ES (P = 0.007). Conclusion SMX/TMP 200/40 mg had a high PCP prevention rate and was superior to SMX/TMP 400/80 mg in terms of drug retention and safety. Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000007727.

Background Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported. Methods Adult patients with systemic rheumatic diseases who started prednisolone ≥0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24. Results Of 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8–100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS ( p  = 0.007). The discontinuation rates due to AEs were significantly lower with HS ( p  = 0.006) and ES ( p  = 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP ( p  = 0.009) and AEs of special interest ( p  = 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES. Conclusions Although there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases. Trial registration The University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727 , registered 10 April 2012.

A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman’s disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman’s disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG-positive plasma cell ratio are recommended if IgG4-related disease is suspected.

Abstract A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman's disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman's disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG-positive plasma cell ratio are recommended if IgG4-related disease is suspected.