First-in-human study to assess the safety, tolerability, and pharmacokinetics of intravenous SHPL-49 following single- and multiple-ascending-dose administration in healthy adults.

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300 mg) and multiple ascending doses (75-300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC0-t) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300 mg.

Modeling opening price spread of Shanghai Composite Index based on ARIMA-GRU/LSTM hybrid model.

In the dynamic landscape of financial markets, accurate forecasting of stock indices remains a pivotal yet challenging task, essential for investors and policymakers alike. This study is motivated by the need to enhance the precision of predicting the Shanghai Composite Index's opening price spread, a critical measure reflecting market volatility and investor sentiment. Traditional time series models like ARIMA have shown limitations in capturing the complex, nonlinear patterns inherent in stock price movements, prompting the exploration of advanced methodologies. The aim of this research is to bridge the gap in forecasting accuracy by developing a hybrid model that integrates the strengths of ARIMA with deep learning techniques, specifically Long Short-Term Memory (LSTM) and Gated Recurrent Unit (GRU) networks. This novel approach leverages the ARIMA model's proficiency in linear trend analysis and the deep learning models' capability in modeling nonlinear dependencies, aiming to provide a comprehensive tool for market prediction. Utilizing a comprehensive dataset covering the period from December 20, 1990, to June 2, 2023, the study develops and assesses the efficacy of ARIMA, LSTM, GRU, ARIMA-LSTM, and ARIMA-GRU models in forecasting the Shanghai Composite Index's opening price spread. The evaluation of these models is based on key statistical metrics, including Mean Squared Error (MSE) and Mean Absolute Error (MAE), to gauge their predictive accuracy. The findings indicate that the hybrid models, ARIMA-LSTM and ARIMA-GRU, perform better in forecasting the opening price spread of the Shanghai Composite Index than their standalone counterparts. This outcome suggests that combining traditional statistical methods with advanced deep learning algorithms can enhance stock market prediction. The research contributes to the field by providing evidence of the potential benefits of integrating different modeling approaches for financial forecasting, offering insights that could inform investment strategies and financial decision-making.

Investigation of Penicillin Binding Protein (PBP)-like Peptide Cyclase and Hydrolase in Surugamide Non-ribosomal Peptide Biosynthesis.

Non-ribosomal peptides (NRPs) are biosynthesized on non-ribosomal peptides synthetase (NRPS) complexes, of which a C-terminal releasing domain commonly offloads the products. Interestingly, a dedicated releasing domain is absent in surugamides (SGM) NRPS, which directs the biosynthesis of cyclic octapeptides, SGM-A to -E, and the linear decapeptide, SGM-F. Here, we confirmed that surE is essential for the production of SGMs via genetic experiments. Biochemical characterization demonstrated that the recombinant enzyme, SurE, can generate the main products SGM-A and -F from the corresponding SNAC substrates, indicating that SurE is a standalone thioesterase-like enzyme. SurE also displays considerable substrate plasticity with expanded ring or different amino acid compositions to produce different cyclopeptides, highlighting the potential of chemoenzymatic applications. Site-directed mutagenesis allowed identification of the key residues of SurE. Finally, bioinformatics analysis suggested that SurE homologs are widely distributed in bacteria, suggesting a general mechanism of NRP release in Nature.

Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers.

PURPOSE: Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices-compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development. METHODS: This 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30mg, followed by edaravone 30mg IV infusion given over 30 minutes; or (2) edaravone 30mg IV infusion given over 30 minutes, followed by SL edaravone 30mg. The washout period between the 2 dosing periods was at least 24hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study. FINDINGS: The plasma concentration-time profile of the SL tablet was similar to that with the IV infusion. Amean (SD) Cmax of 2030.2 (517.2) ng/mL was reached within a median Tmax of 0.875hour, which was statistically significantly longer than the median Tmax with IV administration (0.5 hour). The Cmax with SL administration corresponded to 83.92% (90% CI, 73.22%-96.18%) of the Cmax with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC0-t with SL dosing was 5420.07 (1429.75) h · ng/mL, which corresponded to 91.94% (90% CI, 86.81%-97.39%) of the AUC0-t with IV administration (5824.42 [1338.48] h · ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment. IMPLICATIONS: The bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, Cmax with SL administration was ∼17% lower and Tmax was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone.

Influence of TNF-α and biomechanical stress on matrix metalloproteinases and lysyl oxidases expressions in human knee synovial fibroblasts.

PURPOSE: It was reported that not only ACL but also the synovium may be the major regulator of matrix metalloproteinases (MMPs) in synovial fluids after ACL injury. In order to further confirm whether synovium is capable of regulating the microenvironment in the process of ACL injury, the complicated microenvironment of joint cavity after ACL injury was mimicked and the combined effects of mechanical injury and inflammatory factor [tumour necrosis factor-α (TNF-α)] on expressions of lysyl oxidases (LOXs) and MMPs in synovial fibroblasts derived from normal human synovium were studied. METHODS: Human normal knee joint synovial fibroblasts were stimulated for 1-6 h with mechanical stretch and inflammatory factor (TNF-α). Total RNA was harvested, reverse transcribed and assessed by real-time polymerase chain reaction for the expression of LOXs and MMP-1, 2, 3 messenger RNAs. MMP-2 activity was assayed from the collected culture media samples using zymography. RESULTS: Compared to control group, our results showed that 6% physiological stretch increased MMP-2 and LOXs (except LOXL-3), decreased MMP-1 and MMP-3; injurious stretch (12%) decreased LOXs (except LOXL-2)and increased MMP-1, 2 and 3; the combination of injurious stretch and TNF-α decreased LOXs and increased MMP-1, 2 and 3 in synovial fibroblasts in a synergistical manner. CONCLUSION: This study demonstrated that combination of mechanical injury and inflammatory factors up-regulated the expressions of MMPs and down-regulated the expressions of LOXs in synovial fibroblasts, eventually alter the balance of tissue healing. Thus, synovium may be involved in regulating the microenvironment of joint cavity. Based on the mechanism, early interventions to inhibit the production of MMPs or promote the production of LOXs in the synovial fibroblasts should be performed to facilitate the healing of tissue.