Narrow-band UVB suppresses nasal symptom and H1R mRNA

Background: Phototherapy with narrow-band ultraviolet B (narrow-band UVB) is clinically effective treatment for atopic dermatitis. In the present study, we examined the effects of intranasal irradiation with narrow-band UVB on nasal symptom, upregulation of histamine H1 receptor (H1R) gene expression and induction of DNA damage in the nasal mucosa of allergic rhinitis (AR) model rat. Methods: AR model rats were intranasally irradiated with 310 nm of narrow-band UVB. Nasal mucosal levels of H1R mRNA were measured using real-time quantitative reverse transcriptase (RT)-PCR. DNA damage was evaluated using cyclobutane pyrimidine dimer (CPD) immunostaining. Results: In toluene 2, 4-diisocyanate (TDI)-sensitized rats, TDI provoked sneezes and H1R gene expression in the nasal mucosa. Intranasal pre-irradiation with 310 nm narrow-band UVB at doses of 600 and 1400, but not 200 mJ/cm2 significantly inhibited the number of sneezes and upregulation of H1R gene expression provoked by TDI. CPD-positive cells appeared in the nasal mucosa after intranasal narrow-band UVB irradiation at a dose of 1400, but not 200 and 600 mJ/cm2. The suppression of TDI-provoked sneezes and upregulation of H1R gene expression lasted 24 h, but not 48 h, after narrow-band UVB irradiation with a dose of 600 mJ/cm2. Conclusions: Intranasal pre-irradiation with narrow-band UVB dose-dependently inhibited sneezes and upregulation of H1R gene expression of the nasal mucosa in AR model rats, suggesting that the inhibition of nasal upregulation of H1R gene expression suppressed nasal symptom. The suppression after narrow-band UVB irradiation at a dose of 600 mJ/cm2 was reversible without induction of DNA damage. These findings indicated that low-dose narrow-band UVB phototherapy could be effectively and safely used for AR treatment in a clinical setting

Human placental extract improves liver cirrhosis in mice with regulation of macrophages and senescent cells

Introduction: Cirrhosis is a disease with poor prognosis that requires the development of a novel therapeutic approach alternative to liver transplantation. In this study, we focused on the placenta and aimed to clarify the effects of human placental extract (HPE) on cirrhosis. Methods: A mouse model of carbon tetrachloride-induced cirrhosis was used to evaluate the effect of HPE administration subcutaneously and compared with the control group (n = 8 for each group). In vitro and in vivo, real time-PCR and immunostaining were performed for HPE mechanistic analysis. Spatial transcriptomics was also performed for detailed analysis of the effect of HPE on cirrhosis. Results: HPE administration improved serum ALT levels compared to control mice. Furthermore, there was a decrease in the number of senescent cells in the liver and the mRNA levels of secrete senescence-associated secretory phenotype factors and Cdkn2a (p16). In vitro, HPE induced macrophage polarization to the anti-inflammatory M2 phenotype. Spatial transcriptomics was also performed to analyze the underlying anti-inflammatory mechanism. The results showed that HPE strongly polarized macrophages to the M2 phenotype, especially in macrophage-rich regions in the liver. Gene expression pathway analysis using spatial transcriptomics also revealed the possibility of improving senescent cell-derived inflammation via mitochondrial function. Conclusions: HPE improves serum ALT levels via anti-inflammatory mechanisms in macrophages and senescent cells. HPE serves as a novel agent for cirrhosis treatment

Platelet-rich plasma-derived extracellular vesicles improve liver cirrhosis in mice

Introduction: Cirrhosis remains a significant clinical challenge due to its poor prognosis and limited treatment options, creating a high unmet medical need for the development of novel therapies. In this study, we analyzed the effects of a novel approach to treat cirrhosis using platelet-rich plasma-derived extracellular vesicles (PRPEV) in mice. Methods: PRPEV were collected from platelet-rich plasma using ultrafiltration, and their proteomes were analyzed. The carbon tetrachloride (CCl4)-induced cirrhosis model of mice was used to evaluate the effect of PRPEV administration and compared with the control group (n = 8). In vitro and in vivo mechanistic analyses of PRPEV administration were confirmed using real time-PCR and immunostaining. Results: Gene ontology analysis based on the proteome revealed that PRPEV contain many factors associated with EV and immune responses. In vitro, PRPEV polarize macrophages into an anti-inflammatory phenotype. Following PRPEV administration, there was a decrease in serum alanine aminotransferase levels and reduction in liver fibrosis, while mRNA levels of regenerative factors were upregulated and transforming growth factor β-1 was downregulated. Furthermore, the number of anti-inflammatory macrophages in the liver increased. Conclusions: PRPEV may contribute to hepatocyte proliferation, anti-inflammation, and anti-fibrogenesis in the liver. This novel concept paves the way for cirrhosis treatment

Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective<i>In Vivo</i>without Systemic Immune Activation

AbstractAgonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor-selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad antitumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy.Significance:Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression.See related commentary by Keenan and Fong, p. 20.This article is highlighted in the In This Issue feature, p. 1</jats:sec

Supplementary Data from Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective <i>In Vivo</i> without Systemic Immune Activation

Supplementary figures, tables, material and methods, and references</p

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo