Image_1_Mesenchymal stem cell-derived exosomes for treatment of sepsis.jpeg

IntroductionThe pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis.MethodsAfter recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24 h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury.ResultsThe infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21 h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups.ConclusionWe have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.</p

Associations between maternal clinical features and fetal outcomes in pregnancies of mothers with connective tissue diseases

<p><b>Objectives:</b> The purpose of this study is to clarify associations between maternal clinical features and adverse pregnancy outcomes (APOs) in mothers with connective tissue diseases (CTDs).</p> <p><b>Methods:</b> We retrospectively examined maternal clinical features including backgrounds, autoantibodies, CTD flare-ups, and therapies during pregnancies as well as fetal outcomes in 90 pregnancies (66 mothers) at our hospital from January 2006 to September 2016.</p> <p><b>Results:</b> Underlying CTDs were SLE (<i>N</i> = 41), MCTD (<i>N</i> = 10), RA (<i>N</i> = 15), SS (<i>N</i> = 10), and others (<i>N</i> = 14). Anti-SS-A antibody was detected in 60.3%, lupus anticoagulant (LAC) was in 11.4%, and anti-cardiolipin-β2glycoprotein1 antibody was in 18.5%. Flare-ups of CTDs occurred in 20 pregnancies (22.2%). Corticosteroids (CS) was administered in 73 pregnancies, immunosuppressants in four, and biologics in one. Among the 85 pregnancies other than five early abortions within 12 weeks of gestational age, 33 cases had APOs while the remaining 52 cases were normal. Although disease duration, MCTD, high dose of CS, flare-ups of CTDs, and positive LAC significantly correlated with APOs by univariate analysis, only MCTD was a significant independent predictor for APOs by multivariate analysis.</p> <p><b>Conclusion:</b> Disease duration, MCTD, high dose of CS, flare-ups of CTDs, and LAC might be possible predictive risk factors for APOs in pregnancies with CTDs. Of these, MCTD was a significant independent risk factor.</p

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats