Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts.

Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-ß) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.

Potential probiotic characteristics and genomic analysis of a new folate-producing lactic acid bacteria Lactiplantibacillus plantarum ZFM55.

BACKGROUND: Folate is crucial for maintaining health, but humans are unable to synthesize folate and need to obtain it from food. Lactiplantibacillus plantarum can produce the necessary vitamin B for the human body, including folate. Whole genome sequencing technology can clarify the physiological characteristics of folate production in Lactiplantibacillus plantarum. In order to explore new Lactiplantibacillus plantarum that produce folate, the folate production and probiotic characteristics of Lactiplantibacillus plantarum ZFM55 isolated from infant feces were investigated, and whole genome sequencing was performed. RESULTS: The folate synthesis ability of Lactiplantibacillus plantarum ZFM55 were measured, and its total folate production was 299.72 ± 28.81 ng mL-1. Subsequently, its probiotic properties were explored. The antibacterial test showed that its inhibition zone diameter against Staphylococcus aureus and Salmonella typhimurium was 15.5 ± 0.82 mm and 13.88 ± 0.98 mm, respectively. The tolerance test results indicated that it maintained good activity in simulated gastrointestinal tract and bile salt environments. In vitro intestinal simulation experiments had confirmed that Lactiplantibacillus plantarum ZFM55 can increase the abundance of beneficial bacteria such as Bifidobacteria in the intestine and inhibit the growth of harmful bacteria such as Escherichia_Shigella. Genomic sequencing indicated that the genetic material of Lactiplantibacillus plantarum ZFM55 contains one chromosome and three plasmids, and it has 20 genes related to folate synthesis, which explains its ability to produce folate. CONCLUSION: This study reports a new potential probiotic that produces folate, and provides ideas for exploring probiotics with specific probiotic characteristics. © 2024 Society of Chemical Industry.

Development of novel celastrol-ligustrazine hybrids as potent peroxiredoxin 1 inhibitors against lung cancer.

The disruption of oxidation-reduction equilibrium through inhibiting reactive oxygen species (ROS) clearance or enhancing ROS production has emerged as a novel and promising strategy for cancer therapy. Herein, a series of celastrol-ligustrazine hybrids were designed and synthesized as effective ROS promoters, and their biological activities were further evaluated. Among them, compound 7e stood out as the most potent peroxiredoxin 1 (PRDX1) inhibitor (IC50 = 0.164 µM), which was significant super to the recognized PRDX1 inhibitor Conoidin A (IC50 = 14.80 µM) and the control compound celastrol (IC50 = 1.622 µM). Furthermore, 7e dramatically promoted intracellular ROS accumulation, and inhibited the proliferation, invasion and migration of cancer cells besides inducing apoptosis in vitro. Additionally, 7e suppressed the key signaling pathways (AKT and ERK) and promoted the expression of apoptosis-related proteins (cleaved caspase-3/8 and cleaved PARP) in A549 cells, which resulted in the prevention of tumor progression. Most importantly, compound 7e (TGI = 77.47%) showed more considerable in vivo antitumor efficacy and less toxicity than celastrol (TGI = 71.00%). Overall, this work indicates 7e as the most potential PRDX1 inhibitor and may be a promising candidate for the therapy of lung cancer.

Characteristics of Activation Rate and Damage of Ion-Implanted Phosphorous in 4H-SiC after Different Annealing by Optical Absorption.

We investigated the ellipsometer-based characterization method being used to quickly evaluate the depth of the damage layer in ion-implanted 4H-SiC. This method had the advantages of low cost, convenience, and non-destructiveness. Optical absorption of n-type 4H-SiC substrate, P+ ion-implanted, laser-annealed, and conventional high-temperature annealed wafers were investigated at room temperature. Three peaks were observed in the absorption spectra collected for various samples. The degree of electrical activation after laser annealing or high-temperature annealing was evaluated qualitatively from the absorption peak intensity at 2.67 eV. The circular transmission line method (CTLM) results were consistent with the optical absorption results. However, it was found that the effective carrier concentration after laser annealing was significantly lower than that after high-temperature annealing.

Genetic and immunological characterization of G9 group A porcine rotaviruses in China.

G9 group A rotaviruses (RVAs) are considered emerging pathogens in pigs and humans, and pigs are considered a potential host reservoir for human G9 RVAs. In this study, RVAs of two genotypes, G9P[23] and G9P[13], were successfully isolated and the genomic sequences were obtained, the genome constellation is G9-P[23]-I5-R1-C1-M1-A8-N1-T1-E1-H1 and G9-P[13]-I5-R1-C1-M1-A8-N1-T7-E1-H1 respectively. One strain which amplified from clinic faecal sample had an unique genome constellation G9-P[23]-I1-R1-C1-M1-A8-N1-T1-E1-H1. All the genomic segments of three porcine G9 RVAs were closely related to those of porcine and/or porcine-like human RVAs, demonstrating that the three viruses were porcine-human reassortant strains. To study the immunogenicity of the porcine G9 RVAs, 6-week-old female BALB/c mice were immunized with inactivated vaccines derived from porcine RVAs and then mated. The highest titres of neutralizing antibodies against G9P[23] and G9P[13] porcine RVAs (1,291 ± 35.22 and 1:232 ± 39.28 respectively) were produced in mice 7 days after the second immunization. Suckling mice born to the vaccinated dams were protected by maternal antibodies against challenge with homologous strains. Overall, our data demonstrate the occurrence of porcine-human reassortants of G9 RVAs, and extend our understanding of the immunogenicity of porcine G9 rotaviruses. They also provide a basis for the development of a porcine G9 RVA vaccine.