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c-Jun is a major component of the AP-1 transactivator complex. In this report, we demonstrated that AP-1 was activated by the expression of UL42, a human cytomegalovirus-encoded membrane protein that has two PPXY (PY) motifs and a C-terminal transmembrane domain (TMD). Although UL42 interacts with Itch, an ubiquitin E3 ligase, through the PY motifs, UL42 phosphorylated c-Jun and c-Jun N-terminal kinase (JNK) in the absence of any interaction with Itch. Experiments using mutated versions of UL42 suggest the importance of the carboxyl half (a.a. 52-124) of UL42 for the activation of the JNK signaling, while C-terminal TMD alone is not sufficient. Thus, we hypothesize that UL42 plays a role in the activation of JNK signaling in HCMV-infected cells. (118 words).

Over the past two decades, lactic acid bacteria (LAB) have been intensively studied as potential bacterial carriers for therapeutic materials, such as vaccine antigens, to the mucosal tissues. LAB have several attractive advantages as carriers of mucosal vaccines, and the effectiveness of LAB vaccines has been demonstrated in numerous studies. Research on LAB vaccines to date has focused on whether antigen-specific immunity, particularly antibody responses, can be induced. However, with recent developments in immunology, microbiology, and vaccinology, more detailed analyses of the underlying mechanisms, especially, of the induction of cell-mediated immunity and memory cells, have been required for vaccine development and licensure. In this mini-review, we will discuss the issues, including (i) immune responses other than antibody production, (ii) persistence of LAB vaccine immunity, (iii) comparative evaluation of LAB vaccines with any existing or reference vaccines, (iv) strategies for increasing the effectiveness of LAB vaccines, and (iv) effects of microbiota on the efficacy of LAB vaccines. Although these issues have been rarely studied or discussed to date in relation to LAB vaccine research, further understanding of them is critical for the practical application of LAB vaccine systems.

We conducted a double blind, multi-centric, placebo-controlled, randomized trial to compare the Pressure Ulcer Scale for Healing (PUSH) and Pressure Sore Status Tool (PSST) scores and wound area measurements at 16 weeks of subjects with pressure ulcers who were given standard care plus one of two types of collagen hydrolysate (CH-a), which contained low levels of prolylhydroxyproline (Pro-Hyp) and hydroxyprolylglycine (Hyp-Gly), and CH-b, which contained high levels of Pro-Hyp and Hyp-Gly) with the placebo group. A total of 120 subjects with stage II or III pressure ulcers were entered into the trial and 112 subjects completed the study. The subjects were randomized to receive CH-a (n = 39), CH-b (n = 39), or a placebo (n = 42) twice daily (10 g per day) for 16 weeks. The PUSH score, PSST score, and wound area of the CH-b group were significantly lower than the placebo group at week 16 (PUSH score, P < 0.001; PSST score, P < 0.01; wound area, P < 0.05). The PUSH score of the CH-a group was significantly lower than the placebo group at week 16 (P < 0.05). This study demonstrated that CH-b ingestion helps healing of pressure ulcers as an add-on to the standard therapy.

Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70–80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.

As congenital cytomegalovirus (CMV) infections are the leading non-genetic cause of sensorineural hearing loss and significant neurological disabilities in children, the development of CMV vaccines should be given the highest public health priority. Although MF59-adjuvanted glycoprotein B (gB) vaccine (gB/MF59) is safe and immunogenic, its efficacy in terms of protection from natural infection was around 50 % in clinical trials. Although gB/MF59 induced high antibody titers, anti-gB antibodies contributed little to the neutralization of infection. Recent studies have found that non-neutralizing functions, including antibody-dependent phagocytosis of virions and virus-infected cells, are likely to play important roles in pathogenesis and vaccine design. Previously, we isolated human monoclonal antibodies (MAbs) that reacted with the trimeric form of gB ectodomain and found that preferential epitopes for neutralization were present on Domains (Doms) I and II of gB, while there were abundant non-neutralizing antibodies targeting Dom IV. In this study, we analyzed the phagocytosis activities of these MAbs and found the following: 1) MAbs effective for phagocytosis of the virions targeted Doms I and II, 2) the MAbs effective for phagocytosis of the virions and those of virus-infected cells were generally distinct, and 3) the antibody-dependent phagocytosis showed little correlation with neutralizing activities. Taking account of the frequency and levels of neutralization and phagocytosis, incorporation of the epitopes on Doms I and II into developing vaccines is considered desirable for the prevention of viremia.

Background. Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). Methods. To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. Results. Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in bloodvessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. Conclusions. Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

Direct administration of vaccines to mucosal surfaces, such as via oral or nasal vaccination, represents an attractive alternative, or complement, to current parenteral vaccination because it has a potential to induce antigen-specific immunity both at mucosal and systemic tissues. Although bacterium-like particles (BLPs), peptidoglycan structures derived from lactic acid bacteria, have been investigated as a novel adjuvant for oral or nasal vaccines, it remains unclear whether the administration routes differ the adjuvant effect of BLPs. Here, we showed that the adjuvant effect of BLPs from Lactococcus lactis NZ9000 is greater with the nasal administration than with the oral administration. We conjugated BLPs with Tir, a virulence factor of Citrobacter rodentium , as a model adjuvant-antigen complex, and found that nasal, but not oral, immunization of mice with BLP-Tir induced robust antigen-specific IgA responses at the respiratory and intestinal mucosa, IgG2b-skewed systemic responses, and Th17 cellular responses. As one of the underlying mechanisms, we demonstrated that the nasal administration has a greater delivery efficiency (~1,000-fold) of the BLPs-conjugated antigens to mucosal-associated lymphoid tissues than the oral administration. Furthermore, the nasal, but not oral, administration of BLP-Tir elicited robust innate immune responses that were characterized by the expression of various pro-inflammatory cytokines and chemokines in the mucosal-associated lymphoid tissues. Considering these findings together, we anticipate that BLPs can be an attractive novel adjuvant for nasal vaccines targeting not only respiratory but also gastrointestinal infectious diseases.

This study focuses on the assignment of the 1 H and 13 C NMR spectra of four oleanene- and four ursene-type triterpenes, namely oleanolic acid ( 1 ), ursolic acid ( 2 ), 3- O -acetyloleanolic acid ( 3 ), 3- O -acetylursolic acid ( 4 ), 3- epi -oleanolic acid ( 5 ), 3- epi -ursolic acid ( 6 ), 3- O - epi -acetyloleanolic acid ( 7 ) and 3- O - epi -acetylursolic acid ( 8 ). Various NMR techniques were employed, such as 1D ( 1 H, 13 C), 2D (COSY, 1 H - 13 C COSY, HMQC, HMBC, and INADEQUATE). These advanced approaches enabled the unambiguous assignment of the methyl proton signals and the carbon signals in the triterpene structures. These comprehensive spectral data provide essential reference information for future research on similar compounds from natural or synthetic sources. Graphical Abstract

Methanol extract of the Cnidium officinale Makino rhizome, which is used as a crude drug Cnidium Rhizome ( Cnidii Rhizoma ; “ Senkyu ” in Japanese) and is listed in the Japanese Pharmacopoeia XVIII, showed intracellular triglyceride metabolism-promoting activity in high glucose-pretreated HepG2 cells. Thirty-five constituents, including two new alkylphthalide glycosides, senkyunosides A ( 1 ) and B ( 2 ), and a neolignan with a new stereoisomeric structure ( 3 ), were isolated in the extract. Their stereostructures were elucidated based on chemical and spectroscopic evidence. Among the isolates, several alkylphthalides, ( Z )-3-butylidene-7-methoxyphthalide ( 9 ) and senkyunolides G ( 10 ), H ( 14 ), and I ( 15 ), and a polyacetylene falcarindiol ( 26 ), were found to show significant activity without any cytotoxicity at 10 μM. Graphical abstract

Introduction Pembrolizumab is the standard therapy for urothelial carcinoma treatment; however, adverse events have been noted. Here, we report a rare case of vision loss as an immune‐related adverse event of pembrolizumab therapy in a patient with metastatic renal pelvic cancer. Case presentation A 69‐year‐old man treated with pembrolizumab for lung and lymph node metastases of renal pelvic cancer experienced significant vision loss in both eyes after 11 treatment cycles. Without magnetic resonance imaging confirmation owing to an MRI‐unsafe pacemaker, his clinical features suggested immune checkpoint inhibitor‐associated optic neuritis. Pembrolizumab was discontinued, and the patient received steroid pulse and immunoglobulin therapy. His vision in the right eye improved, but that in the left eye remained unchanged. He maintained a partial response for 36 months despite pembrolizumab discontinuation. Conclusion Despite its rarity, vision loss is a potential irAE in patients treated with ICIs, including pembrolizumab.