SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study.

Objective: To investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF. Methods: Applying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium. Results: SGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [ß = -0.20, 95% CI (-0.39, -0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF. Conclusion: The study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.

Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination.

Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.

Detracking Autoencoding Conditional Generative Adversarial Network: Improved Generative Adversarial Network Method for Tabular Missing Value Imputation.

Due to various reasons, such as limitations in data collection and interruptions in network transmission, gathered data often contain missing values. Existing state-of-the-art generative adversarial imputation methods face three main issues: limited applicability, neglect of latent categorical information that could reflect relationships among samples, and an inability to balance local and global information. We propose a novel generative adversarial model named DTAE-CGAN that incorporates detracking autoencoding and conditional labels to address these issues. This enhances the network's ability to learn inter-sample correlations and makes full use of all data information in incomplete datasets, rather than learning random noise. We conducted experiments on six real datasets of varying sizes, comparing our method with four classic imputation baselines. The results demonstrate that our proposed model consistently exhibited superior imputation accuracy.

Otitis media with effusion in adults during the SARS-CoV-2 epidemic.

OBJECTIVES: The purpose of this study was to investigate the fluctuations in the prevalence of individuals diagnosed with otitis media with effusion (OME) during the SARS-CoV-2 pandemic, while also evaluating the persistence of SARS-CoV-2 in middle ear effusion (MEE) and assessing the effectiveness of tympanocentesis as a treatment modality for OME in this specific period. METHODS: The total number of outpatients and patients diagnosed with OME in our department was recorded for January 2022 and January 2023. Thirty patients (aged 15-86 years) were categorized into two groups: group A (n = 12), who developed OME during their SARS-CoV-2 infection and group B (n = 18), who experienced OME after the resolution of SARS-CoV-2 infection. All patients underwent otoendoscopic tympanocentesis (without a ventilation tube), where MEE and nasopharyngeal secretions were simultaneously collected for SARS-CoV-2 detection by polymerase chain reaction. The time interval from SARS-CoV-2 infection to tympanocentesis, results of SARS-CoV-2 detection, preoperative and postoperative average hearing threshold, and Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores were documented. RESULTS: The proportion of outpatients with OME in January 2023 was higher than that in January 2022. There were five patients who had positive test results for SARS-CoV-2 on MEE after tympanocentesis. These 5 patients underwent tympanocentesis at a mean of 28 ± 7.28 days following confirmation of SARS-CoV-2 infection. The ETDQ-7 scores of group A exhibited a reduction from 21.85 ± 4.8 to 10.00 ± 4.07 following tympanocentesis, while the ETDQ-7 scores of group B also demonstrated a decrease from 21.22 ± 4.65 to 10.11 ± 3.68 after undergoing tympanocentesis. The tympanocentesis was effective in both groups. CONCLUSIONS: The study confirmed that the proportion of outpatients with OME in the Clinics of Otolaryngology during the SARS-CoV-2 epidemic increased significantly. SARS-CoV-2 RNA was detectable in MEE of COVID-19-related OME patients. Tympanocentesis was therapeutic for OME during SARS-CoV-2 infection, which facilitated viral clearance in MEE.

Safety, pharmacokinetics, and efficacy of rifasutenizol, a novel dual-targeted antibacterial agent in healthy participants and patients in China with Helicobacter pylori infection: four randomised clinical trials.

BACKGROUND: Due to the rapid development of antimicrobial resistance, the efficacy of most Helicobacter pylori eradication therapies have progressively decreased to an unacceptable level. Rifasutenizol (TNP-2198) is a new molecular entity with a synergistic dual mechanism of action currently under clinical development for the treatment of microaerophilic and anaerobic bacterial infections. We aimed to evaluate the safety, pharmacokinetics, and efficacy of rifasutenizol in healthy Chinese participants and patients with H pylori. METHODS: We conducted four clinical trials of rifasutenizol capsules in healthy participants (aged 18-55 years) and patients with asymptomatic H pylori infection (aged 18-65 years) in a clinical trial centre in Jilin province, China. Trial 1 was a phase 1, double-blind, randomised, placebo-controlled, single ascending dose study, in which participants were enrolled into one of seven rifasutenizol dose groups (50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg) and were randomly assigned in a 4:1 ratio to study drug or placebo. Trial 2 was a phase 1, double-blind, randomised, placebo-controlled, multiple ascending dose study, in which patients were enrolled into one of three rifasutenizol dose groups (200 mg, 400 mg, or 600 mg) and were randomly assigned in a 3:1 ratio to study drug or placebo. Trial 3 was a phase 2a, open-label, randomised, multiple-dose, dose-finding study in which patients enrolled into one of four cohorts were randomly assigned in a 1:1:1:1 ratio to a rifasutenizol dual or triple regimen. Trial 4 was a phase 2b, open-label, randomised, multiple-dose, regimen exploration study, in which patients enrolled into one of five cohorts were randomly assigned in a 2:2:1:1:2 ratio to a rifasutenizol dual therapy, triple therapy, or a control cohort. Block randomisation (block size 4 or 8) was used in all four trials. The key primary endpoints for trials 1, 2, and 3 were the tolerability, safety, and pharmacokinetics of rifasutenizol. For trial 4, the primary endpoint was the eradication rate of H pylori. These four trials were registered at ClinicalTrials.gov (NCT06081699, NCT06081712, NCT06076681, and NCT06076694) and chinadrugtrials.org.cn (CTR20190734, CTR20192553, CTR20212050, and CTR20220625) and are completed. FINDINGS: Between May 9, 2019, and Sept 14, 2022, 78 healthy participants (trial 1: n=10 per cohort in a 4:1 rifasutenizol:placebo ratio; and an additional eight for the food-effect cohort) and 168 patients with asymptomatic H pylori infection (trial 2: n=16 per cohort in a 3:1 rifasutenizol:placebo ratio; trial 3: n=10 per cohort; trial 4: n=10 or n=20 per cohort) were enrolled in the four clinical trials. Single doses of rifasutenizol (50-1000 mg) and multiple doses of rifasutenizol (200 mg to 600 mg, twice a day), either as monotherapy or co-administered with rabeprazole and amoxicillin, showed favourable safety and tolerability profiles. Most adverse events were mild, and no serious adverse events were reported. Rifasutenizol demonstrated a linear pharmacokinetic profile over the dose range of 50-800 mg, and there were no apparent pharmacokinetic interactions between rifasutenizol and the co-administrated drugs. Food intake slightly elevated the area under the plasma concentration-time curve (AUC) of rifasutenizol, and the geometric mean of AUC from time 0 to the last timepoint with a quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) in the fed state were 1·334 and 1·396 times of those in the fasted state, respectively. There was mild accumulation after continuous administration of rifasutenizol, and the Rac(AUC) of rifasutenizol 400 mg in the dual and triple regiments in trial 3 were 1·37 and 1·49, respectively. In trial 3, the eradication rates of H pylori with 200 mg, 400 mg, or 600 mg of rifasutenizol in combination with rabeprazole, twice a day for 14 days, were 0% (95% CI 0-31), 30% (7-65), and 40% (12-74), respectively, identifying rifasutenizol 400 mg as the effective dose. In trial 4, H pylori eradication rates with the triple regimen in cohort A (400 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) twice a day for 14 days was 95% (95% CI 74-100), and triple therapy (600 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) three times a day for 7 days was 100% (69-100). INTERPRETATION: Rifasutenizol monotherapy and combination therapy was generally safe and well tolerated in healthy participants and patients with H pylori infection. A triple regimen of 400 mg rifasutenizol capsules, 20 mg rabeprazole sodium enteric-coated tablets, and 1 g amoxicillin capsules twice a day for 14 days showed promising efficacy as a new treatment regimen for H pylori infection. FUNDING: TenNor Therapeutics and National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Oropharyngeal Stenosis Caused by Significant Scar Hyperplasia Following Tonsillectomy: A Case Report.

Oropharyngeal stenosis (OPS) is a relatively rare long-term complication of tonsillectomy in children, resulting from the narrowing of the upper aerodigestive tract between the soft palate, pharyngeal sidewalls, and base of the tongue. This is the first reported case of OPS due to significant scar hyperplasia; however, whether it is as prone to recurrence as skin scar hypertrophy remains unknown. In this article, we present the case of a 5-year-old girl who presented to our otolaryngology clinic with sleep snoring and suffocation. Her medical history included tonsillectomy and adenoidectomy, performed 3 years prior to presentation. The patient underwent a combination of surgery and administration of triamcinolone injections, resulting in significant symptomatic improvement. To date, no signs of recurrence have been reported.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Anti-IFNAR1 Monoclonal Antibody QX006N: A First-in-Human Single Ascending Dose Study in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: QX006N is a novel, humanized, IgG4κ monoclonal antibody targeting IFNAR1, developed for the treatment of systemic lupus erythematosus. This study aims to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of QX006N when administered intravenously to healthy Chinese individuals. METHODS: A double-blind, randomized, placebo-controlled, single-ascending-dose, phase I clinical trial was conducted comprising five cohorts (n = 10 per cohort, except n = 5 for the first cohort). Subjects in each cohort were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of QX006N (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 6.0 mg/kg, or 10.0 mg/kg) or placebo for 30 minutes. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. The serum concentration of QX006N was measured using the enzyme-linked immunosorbent assay method, and the anti-drug antibodies were detected using the electrochemiluminescence assay method. RESULTS: QX006N demonstrated a favorable safety and tolerability profile throughout the study. All treatment-emergent adverse events were of Grade 1-2 (CTCAE Version 5.0), and no serious adverse events, deaths, or drug discontinuations because of treatment-emergent adverse events were observed. All drug-related treatment-emergent adverse events showed no clear dose-related trends. Following an intravenous infusion of QX006N at doses that ranged from 0.3 mg/kg to 10 mg/kg, the half-life increased from 24.7 to 208 hours in a dose-dependent manner, while clearance decreased from 0.0828 to 0.0065 L/h. The maximum concentration exhibited nearly dose-proportional increases, and the area under the curve displayed a more than dose-proportional increment with non-linear pharmacokinetic characteristics. The incidence of anti-drug antibodies was observed to increase over time for doses that ranged from 1.0 mg/kg to 10.0 mg/kg of QX006N, reaching its peak at day 57 (range 62.50-87.50%). Conversely, the incidence of anti-drug antibodies in the QX006N 0.3-mg/kg and placebo cohorts remained low. CONCLUSIONS: QX006N demonstrated acceptable safety, tolerability, and pharmacokinetic characteristics in healthy subjects when administered as a single intravenous infusion at doses that ranged from 0.3 mg/kg to 10.0 mg/kg. Based on the pharmacokinetic and safety outcomes, a recommended effective dose of 300 mg is proposed for future phase Ib studies. CLINICAL TRIAL REGISTRATION: This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20212834.

Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

Association between neutrophil-to-lymphocyte ratio and postoperative fatigue in elderly patients with hip fracture.

Background: and purpose: Postoperative fatigue (POF) is a common and distressing post-operative symptom. This study aimed to explore the relationship between neutrophil-to-lymphocyte ratio (NLR) and POF in elderly patients with hip fracture. Method: Elderly patients (age ≥65 years) with acute hip fracture admitted to the Department of Orthopedics of Anqing Municipal Hospital from June 2018 to June 2020 were included. Fatigue was assessed using the Fatigue Severity Scale at the 3-month follow-up postoperatively. Univariate and multivariate analyses were performed to explore the associations between NLR and POF. The diagnostic performance of NLR was analysed using Receiver Operating Characteristic (ROC) curve analysis and the Delong test. Result: A total of 321 elderly patients with hip fractures were included; 120 (37.4 %) of them were diagnosed with POF. Univariate analysis indicated significant differences in NLR, platelet-to-lymphocyte ratio (PLR), education, neutrophil count, lymphocyte count, Hamilton Depression Scale (HAMD) and Insomnia Severity Index (ISI) scores (P < 0.05). Multivariate analysis indicated neutrophil count (odds ratio [OR], 1.46; 95 % confidence interval [CI] 1.27-1.67), lymphocyte count (OR 0.32, 95 % CI 0.19-0.53), NLR (OR1.81, 95 % CI 1.50-2.17) and PLR (OR 1.005, 95 % CI 1.001-1.009) were significantly associated with POF. The areas under the ROC curves (AUCs) of neutrophil count, lymphocyte count, NLR and PLR were 0.712, 0.667, 0.775 and 0.605, respectively. The Delong test indicated that NLR had the best diagnostic performance (p < 0.05). Conclusion: NLR independently predicts POF in elderly patients with acute hip fracture.

COVID-19-related secretory otitis media in the omicron era: a case series.

OBJECTIVES: Increased numbers of patients with secretory otitis media appeared in outpatient clinics after the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron pandemic; however, the relationship between SARS-CoV-2 Omicron variant infection and secretory otitis media is uncertain. METHODS: We performed tympanocentesis and used reverse transcription-polymerase chain reaction (RT-PCR) testing to examine middle ear effusion (MEE) and nasopharyngeal secretions from 30 patients with secretory otitis media associated with SARS-CoV-2 infection. RT-PCR was performed using the open reading frame 1ab and nucleocapsid protein gene kit from Shanghai Berger Medical Technology Co., Ltd., as the sole assay method, in accordance with the manufacturer's instructions. RESULTS: MEEs from 5 of the 30 patients tested positive for SARS-CoV-2, including one patient with positive results for both the nasopharyngeal secretion and MEE. We report and discuss the medical records of six patients, including these five MEE-positive patients and a MEE-negative patient. CONCLUSION: SARS-CoV-2 RNA can be detected in MEE caused by coronavirus disease 2019-related secretory otitis media even when a patient's nasopharyngeal secretion tests PCR-negative for SARS-CoV-2. The virus can remain in the MEE for a long time after SARS-CoV-2 infection.

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

Design, synthesis, antifungal activity and molecular docking of ring-opened pimprinine derivative containing (thio)amide structure.

BACKGROUND: To obtain new environmentally friendly fungicides, we used the natural product pimprinine as the lead compound, and designed and synthesized two series of ring-opening derivatives of pimprinine containing amide/thioamide. We then studied their antifungal activity against six common plant pathogenic fungi in vitro. RESULTS: Most of the target compounds have good antifungal activity against six important plant pathogenic fungi in vitro. At a concentration of 50 µg ml-1 , compound 3o showed prominent antifungal effects on Alternaria solani and Rhioctornia solani, with inhibition rates of 91.8% and 97.4%, and a 50% effective concentration (EC50 ) of 6.2255 and 0.6969 µg ml-1 respectively. The EC50 of compound 3o against Alternaria solani was significantly lower than that of boscalid (13.0380 µg ml-1 ) and flutriafol (11.9057 µg ml-1 ). In addition, compound 3o had good antifungal activity against Sclerotinia sclerotiorum, cucumber powdery mildew, cucumber Botrytis cinerea and Phytophthora capsici in vivo; the antifungal activity of compound 3o against cucumber Botrytis cinerea is 91.7%. At the same time, docking results for highly active compound 3o with the presumed target succinate dehydrogenase and the molecular docking prediction scores of all compounds further indicate its possible antifungal activity mechanism. CONCLUSION: The designed and optimized derivative 3o of ring-opening pimprinine has good antifungal activity and can be used as a new antifungal drug for further research. © 2023 Society of Chemical Industry.

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate-it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 µg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

The effect of a single escalating dose of long-acting recombinant human follicle-stimulating hormone Fc fusion protein (KN015) on healthy, pituitary-suppressed women: first-in-human and randomized study on its pharmacokinetics, pharmacodynamics, and tolerability.

OBJECTIVE: KN015 is a long-acting, recombinant human follicle-stimulating hormone Fc fusion protein that induces follicle development. This first-in-human study evaluated the effect of KN015 on healthy, pituitary-suppressed women and examined its pharmacokinetics, pharmacodynamics, and tolerability. METHODS: This phase I study was a double-blind, randomized, and placebo-controlled design with a single ascending dose (20, 40, and 60 µg, respectively). RESULTS: After subcutaneous administration of a single dose, the maximum serum KN015 concentrations reached 1.57, 2.78, and 3.62 ng/mL, respectively, after baseline adjustment. Over this dose range, the median Tmax occurred at 240-312 h, and the half-life (t½) was 752-1160 h. Dose proportionality was shown across the studied dose range. In most subjects, follicular growth was observed, and the number and diameter of the follicles increased with an increasing dose. In the 40-µg and 60-µg groups, the mean numbers of follicles with a diameter of ≥17 mm were 3 and 4, respectively. There was no significant difference in adverse events between the KN015 and placebo groups. KN015 antibody was not detected in any of the dosage groups. CONCLUSION: The administration of a single ascending dose of KN015 was tolerated and able to induce follicular growth. TRIAL REGISTRATION: This trial is registered at the Chinese Clinical Trials website (http://www.chinadrugtrials.org.cn/index.html # CTR20160741) and ClinicalTrials.gov (https://clinicaltrials.gov/ # NCT03192527).

Discovery of Novel Pimprinine and Streptochlorin Derivatives as Potential Antifungal Agents.

Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this study, pimprinine and streptochlorin were used as parent structures with the combination strategy of their structural features. Three series of target compounds were designed and synthesized. Subsequent evaluation for antifungal activity against six common phytopathogenic fungi showed that some of thee compounds possessed excellent effects, and this is highlighted by compounds 4a and 5a, displaying 99.9% growth inhibition against Gibberella zeae and Alternaria Leaf Spot under 50 µg/mL, respectively. EC50 values indicated that compounds 4a, 5a, 8c, and 8d were even more active than Azoxystrobin and Boscalid. SAR analysis revealed the relationship between 5-(3'-indolyl)oxazole scaffold and antifungal activity, which provides useful insight into the development of new target molecules. Molecular docking models indicate that compound 4a binds with leucyl-tRNA synthetase in a similar mode as AN2690, offering a perspective on the mode of action for the study of its antifungal activity. These results suggest that compounds 4a and 5a could be regarded as novel and promising antifungal agents against phytopathogens due to their valuable potency.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.

BACKGROUND: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. RESEARCH DESIGN AND METHODS: This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. RESULTS: In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). CONCLUSIONS: Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Generation of an induced pluripotent stem cell lines HMSCASTi001-A from peripheral blood mononuclear cells of a 35-year-old healthy male.

Peripheral blood mononuclear cells derived from a 35-year-old healthy male were reprogrammed into induced pluripotent stem cells (iPSCs). The iPSCs maintained a normal karyotype, expressed various pluripotency stem cell markers, and showed potential of differentiating into three germ layers. This iPSCs could be differentiated into multiple cell subtypes for drug discovery and investigation of mechanisms.

Generation of an induced pluripotent stem cell lines HMSCASTi002-A from peripheral blood mononuclear cells of a 38-year-old healthy female individual.

Peripheral blood mononuclear cells (PBMCs) of a 38-year-old healthy female were isolated and reprogrammed into the induced pluripotent stem cells (iPSCs). The established iPSC line expressed various pluripotency stem cell markers and potential of differentiating into three germ layers, meanwhile maintained normal karyotype.

Inulin-type fructans change the gut microbiota and prevent the development of diabetic nephropathy.

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease, and few treatment options that prevent the progressive loss of renal function are available. Studies have shown that dietary fiber intake improves kidney diseases and metabolism-related diseases, most likely through short-chain fatty acids (SCFAs). The present study aimed to examine the protective effects of inulin-type fructans (ITFs) on DN through 16 S rRNA gene sequencing, gas chromatographymass spectrometry (GCMS) analysis and fecal microbiota transplantation (FMT). The results showed that ITFs supplementation protected against kidney damage in db/db mice and regulated the composition of the gut microbiota. Antibiotic treatment and FMT experiments further demonstrated a key role of the gut microbiota in mediating the beneficial effects of ITFs. The ITFs treatment-induced changes in the gut microbiota led to an enrichment of SCFA-producing bacteria, especially the genera Akkermansia and Candidatus Saccharimonas, which increased the fecal and serum acetate concentrations. Subsequently, acetate supplementation improved glomerular damage and renal fibrosis by attenuating mitochondrial dysfunction and reducing toxic glucose metabolite levels. In conclusion, ITFs play a renoprotective role by modulating the gut microbiota and increasing acetate production. Furthermore, acetate mediates renal protection by regulating glucose metabolism, decreasing glycotoxic product levels and improving mitochondrial function.

Introducing SuFEx click chemistry into aliphatic polycarbonates: a novel toolbox/platform for post-modification as biomaterials.

As a biodegradable and biocompatible biomaterial, aliphatic polycarbonates (APCs) have attracted substantial attention in terms of post-polymerization modification (PPM) for functionalization. A strategy for the introduction of sulfur(VI)-fluoride exchange (SuFEx) click chemistry into APCs for PPM is proposed for the first time in this work. 4'-(Fluorosulfonyl)benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (FMC) was designed as a SuFEx clickable cyclic carbonate for APCs via ring-opening polymerization (ROP), and an operational and nontoxic synthetic route was achieved. FMC managed to undergo both ROP and PPM through the SuFEx click chemistry organocatalytically without constraining or antagonizing each other, using 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) as a co-organocatalyst here. Its ROP was systematically investigated, and density functional theory (DFT) calculations were performed to understand the acid-base catalytic mechanism in the anionic ROP. Exploratory investigations into PPM by SuFEx of poly(FMC) were conducted as biomaterials, and the one-pot strategies to achieve both ROP and SuFEx were confirmed.