Explore the vast range of titles available.

Selenoprotein P (SeP) functions as a selenium (Se)-supply protein. SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. Thus, the suppression of Se-supply activity of SeP might improve glucose metabolism. Here, we develop an anti-human SeP monoclonal antibody AE2 as with neutralizing activity against SeP. Administration of AE2 to mice significantly improves glucose intolerance and insulin resistance that are induced by human SeP administration. Furthermore, excess SeP administration significantly decreases pancreas insulin levels and high glucose-induced insulin secretion, which are improved by AE2 administration. Epitope mapping reveals that AE2 recognizes a region of human SeP adjacent to the first histidine-rich region (FHR). A polyclonal antibody against the mouse SeP FHR improves glucose intolerance and insulin secretion in a mouse model of diabetes. This report describes a novel molecular strategy for the development of type 2 diabetes therapeutics targeting SeP. Selenoprotein P is secreted by the liver and when present in excess it promotes development of type 2 diabetes. Here the authors develop neutralizing antibodies to target human and mouse selenoprotein P, and show that they improve insulin secretion and glucose tolerance in mouse models.

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 3 , 4 . This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) 5 , 6 , 7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1) 8 . SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation 9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a ) 10 expression in skeletal muscle. Supplementation with the anti-oxidant N -acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle—effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP–LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

Adjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known. To characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component. This study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.

Squalene-based adjuvants are widely utilized in various vaccines because of their effectiveness in enhancing immune responses. Among these, A-910823 and AS03 are recognized squalene-based adjuvants containing α-tocopherol. Although α-tocopherol-containing squalene-based adjuvants are known to enhance humoral immune responses and inflammatory cytokine production, their underlying mechanisms remain unclear. Here, we found that A-910823 regulated IL-1 signaling pathway gene expression and IL-1α and IL-1β protein expressions in an α-tocopherol-dependent manner. While the source of IL-1α was mainly from eosinophils, IL-1β was from a wide range of myeloid cells. Mechanistically, IL-1β/CD11c + cell-IL-1R1/MyD88 axis mediated adjuvant efficacy, however, systemic reactogenicity was induced by the IL-1β/IL-1R1/MyD88/IL-6/cyclooxygenase 2 axis, which was an unexpectedly distinct mechanism from the local reactogenicity that was mediated by the eosinophil-derived IL-1α/IL-1R1/MyD88 axis. These findings demonstrate that adjuvant efficacy and reactogenicity are regulated by distinct pathways and cell types. This study thus provides novel insights into the mechanisms of adjuvants, providing valuable information to support the future development of effective and safe vaccines.

Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.

Generally, the number of single-nucleotide variants (SNVs) in somatic cells increases with age, which is expected for replication errors. The number of SNVs in cancer cells, however, is often much higher than that in somatic cells, raising the question of whether cancer cells possess SNV induction pathways. The present study shows that the number of SNVs in cancer cells correlates with the number of chromosomal structural variants (SVs). While Kataegis, localized hypermutations typically arising near SV sites, revealed multiple SNVs within 1 kb, SV-associated SNVs were generally observed within 0.1–1 Mb of SV sites, irrespective of Kataegis status. SNVs enriched within 1 Mb of SV regions were associated with deficiency of DNA damage repair, including HR deficiency-associated single base substitution 3 (SBS3) and exogenous damage-associated SBS7 and SBS36 signatures. We also observed a similar correlation between SVs and SNVs in cells that had undergone clonal evolution in association with genomic instability, implying an association between genomic instability and SV-associated induction of SNVs.

Long-persistent luminescence (LPL) materials have applications from safety signage to bioimaging; however, existing organic LPL (OLPL) systems do not align with human scotopic vision, which is sensitive to blue light. We present a strategy to blueshift the emissions in binary OLPL systems by upconverting the charge-transfer (CT) to a locally excited (LE) singlet state. Through rigorous steady-state and time-resolved photoluminescence spectroscopy and wavelength-resolved thermoluminescence measurements, we provide the direct experimental evidence for this upconversion in OLPL systems featuring small energy offsets between the lowest-energy CT and LE singlet states. These systems exhibited strong room temperature LPL, particularly when extrinsic electron traps are added. Importantly, the developed OLPL system achieved Class A (ISO 17398) LPL, matching well with human scotopic vision. The findings not only elucidate the role of small energy offsets in modulating LPL but also provide potential avenues for enhancing the efficiency and applicability of OLPL materials. Existing organic long-persistent luminescence systems do not align with human scotopic vision. Here, authors achieve blue-shifted emissions in binary systems by upconverting charge-transfer to locally excited singlet state, with a strong luminescence under international standard for safety signs.

ObjectivesDiagnosis of cardiac sarcoidosis (CS) without histological evidence remains controversial. This study aimed to compare characteristics and outcomes of histologically proven versus clinically diagnosed cases of CS, which were adjudicated using Heart Rhythm Society or Japanese Circulation Society criteria.MethodsA total of 512 patients with CS (age: 62±11 years, female: 64.3%) enrolled in the multicentre registry were studied. Histologically confirmed patients were classified as ‘biopsy-proven CS’, while those with the presence of strongly suggestive clinical findings of CS without histological evidence were classified as ‘clinical CS’. Primary outcome was a composite of all-cause death, heart failure hospitalisation and ventricular arrhythmia event.ResultsIn total, 314 patients (61.3%) were classified as biopsy-proven CS, while 198 (38.7%) were classified as clinical CS. Patients classified under clinical CS were associated with higher prevalence of left ventricular dysfunction, septal thinning, and positive findings in fluorodeoxyglucose-positron emission tomography or Gallium scintigraphy than those under biopsy-proven CS. During median follow-up of 43.7 (23.3–77.3) months, risk of primary outcome was comparable between the groups (adjusted HR: 1.24, 95% CI: 0.88 to 1.75, p=0.22). Similarly, the risks of primary outcome were comparable between patients with clinical isolated CS who did not have other organ/tissue involvement, and biopsy-proven isolated CS (adjusted HR: 1.23, 95% CI: 0.56 to 2.70, p=0.61).ConclusionsA substantial number of patients were diagnosed with clinical CS without confirmatory biopsy. Considering the worse clinical outcomes irrespective of the histological evidence, the diagnosis of clinical CS is justifiable if imaging findings suggestive of CS are observed.

Malignancy is often associated with therapeutic resistance and metastasis, usually arising after therapeutic treatment. These include radio- and chemo-therapies, which cause cancer cell death by inducing DNA double strand breaks (DSBs). However, it is still unclear how resistance to these DSBs is induced and whether it can be suppressed. Here, we show that DSBs induced by camptothecin (CPT) and radiation jeopardize genome stability in surviving cancer cells, ultimately leading to the development of resistance. Further, we show that cytosolic DNA, accumulating as a consequence of genomic destabilization, leads to increased cGAS/STING-pathway activation and, ultimately, increased cell migration, a precursor of metastasis. Interestingly, these genomic destabilization-associated phenotypes were suppressed by the PARP inhibitor Olaparib. Recognition of DSBs by Rad51 and genomic destabilization were largely reduced by Olaparib, while the DNA damage response and cancer cell death were effectively increased. Thus, Olaparib decreases the risk of therapeutic resistance and cell migration of cells that survive radio- and CPT-treatments.