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Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices.

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%–19% in rats and 45%–51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.

The aim of the present study is to investigate the quantitative effects of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on the quality of life in heart failure (HF) patients. A total of 14,674 HF patients from two dapagliflozin and three empagliflozin studies is included for analysis via the nonlinear mixed-effect modeling (NONMEM) software, among which the change rate of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score is used as the evaluation index. There is no significant difference in the pharmacodynamics influencing the quality of life in HF patients between the SGLT-2 inhibitors: 10 mg/day dapagliflozin and 10 mg/day empagliflozin. For the clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS), the Emax of the SGLT-2 inhibitors on the quality of life in HF patients is 3.74%, 4.43%, and 4.84%, respectively, and ET50 is 2.23, 4.37, and 7.15 weeks, respectively. In addition, the time duration of achieving 25%, 50%, 75%, and 80% Emax is 0.75, 2.23, 6.69, and 8.92 weeks for the CSS; 1.46, 4.37, 13.11, and 17.48 weeks for the TSS; and 2.39, 7.15, 21.45, and 28.6 weeks for the OSS, respectively. Therefore, to reach the plateau period (80% of Emax) of SGLT-2 inhibitors on the CSS, TSS, and OSS, 10 mg/day dapagliflozin (or 10 mg/day empagliflozin) is required to be taken for 8.92 weeks, 17.48 weeks, and 28.6 weeks, respectively. This is the first time that the quantitative effects of SGLT-2 inhibitors on the quality of life in HF patients are being explored.

The development of an effective pharmacological countermeasure is needed to reduce the morbidity and mortality in high-dose ionizing radiation-induced acute damage. Genistein has shown bioactivity in alleviating radiation damage and is currently synthesized by chemosynthetic methods. Due to concerns about chemical residues and high costs, the clinical application of genistein is still a major challenge. In this study, we aimed to establish an efficient method for the extraction of genistein from Fructus sophorae. The effects of extracted genistein (FSGen) on preventing intestinal injury from radiation were further investigated in this study. C57/BL mice were exposed to 7.5 Gy whole body irradiation with and without FSGen treatments. Histological analysis demonstrated significant structural and functional restitution of the intestine and bone marrow in FSGen-pretreated cohorts after irradiation. Through mRNA expression, protein expression, and small interfering RNA analyses, we demonstrated that FSGen protects IEC-6 cells against radiation damage by upregulating the Rassf1a and Ercc1 genes to effectively attenuate DNA irradiation damage. Together, our data established an effective method to extract genistein from the Fructus sophorae plant with high purity, and validated the beneficial roles of the FSGen in protecting the radiation damage. These results promise the future applications of Fructus sophorae extracted genistein in the protection of radiation related damages.

Gardeniae Fructus (GF) and carbonized GF (GFC) have been shown to exert a gastrointestinal protective effect and are frequently used in clinical practice for the treatment of hemorrhage and brown stool. In this study, we employed a combination of pharmacological methods and metabolomics in a rat model of ethanol-induced acute stomach ulcer to investigate the gastroprotective effect of GF and GFC water extracts and the potential mechanism involved in this process. The levels of nitric oxide (NO) and interleukin 6 (IL-6) in the plasma of rats were determined. The results showed that both GF and GFC reduced the ethanol-induced gastric lesions and expression of NO and IL-6 in these rats. Of note, 16 and 11 feature metabolites were filtered and identified in the GF and GFC groups, respectively. Both GF and GFC act by restoring the biosynthesis of valine, leucine, and isoleucine, and the metabolism of glycerophospholipids. Moreover, histological evaluation revealed that heat processing of GF to create GFC enhanced the gastric mucosa protective effect. Furthermore, heat processing converted the main pathway from alanine, aspartate, and glutamate metabolism, associated with GF, to histidine metabolism, associated with GFC. GF and GFC ameliorated gastric mucosa lesions in rats via reductions in NO production and inflammatory cytokine secretion, and the induction of prostaglandin E2.

Gardeniae Fructus (GF), prepared GF (GFP), and carbonized GF (GFC) are widely used in China for the treatment of fever. However, the involved antipyretic mechanism has not been fully elucidated. In this study, rectal temperature and pyrogenic cytokines were used to evaluate the antipyretic effect of raw and processed GF in rats with dry-yeast-induced pyrexia. Reverse phase and hydrophilic interaction liquid chromatography and ultra-high-performance liquid chromatography/mass spectrometry were used to acquire the metabolomics profile of GF, GFP, and GFC in rats with pyrexia. The results showed that the rectal temperature of rats treated with GF, GFP, and GFC was suppressed after 6 h (P < 0.05), compared with that observed in pyrexia model rats. The enzyme-linked immunosorbent assay showed that the expression of tumor necrosis factor α and interleukin 6 were suppressed by GF, GFP, and GFC. Moreover, GFC suppressed the expression of interleukin 6 significantly (P < 0.01). Of note, 11, 15, and 25 feature metabolites were identified in the GF, GFP, and GFC groups. Pathway analysis showed that GF mainly regulated the biosynthesis of valine, leucine, and isoleucine. Notably, GFP was involved in glycerophospholipid metabolism, while GFC was linked to glycerophospholipid and sphingolipid metabolism. These results suggested that GF, GFP, and GFC maintained their antipyretic effect despite heat processing. However, heat processing altered endogenous feature metabolites and certain pathways of GF, GFP, and GFC in rats with yeast-induced pyrexia to exert an antipyretic effect.