Novel chiral matrine derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Since the thalidomide incident, research on chiral drugs has escalated immensely. Differences in drug configuration can lead to significant variations in therapeutic efficacy. Matrine, a natural product esteemed for its low toxicity and high water solubility, has garnered significant attention in research endeavors. Nonetheless, its precise target has proven elusive. In this study, we designed and synthesized a novel chiral matrine derivative. Their cytotoxicity against three types of tumor cells was assessed. Comparing the newly synthesized derivatives to the parent matrine, most compounds exhibited significantly enhanced inhibitory effects on cancer cells. Among them, Q12 exhibited the highest activity, with IC50 values of 8.31 µM against rat glioma cells C6, 6.3 µM against human liver cancer cells HepG2 and 7.14 µM against human gastric cancer cells HGC-27, meanwhile showing low toxicity. Based on IC50 values, we constructed a preliminary structure-activity relationship (SAR). Compound Q12 significantly suppressed the cloning and migration of HepG2 cells. Further mechanistic studies indicated that Q12 inhibited Topo I in HepG2 cells, leading to DNA damage, induction of G0/G1 cell cycle arrest and ultimately causing apoptosis. The molecular docking experiments provided a rational binding mode of Q12 with the Topo I-DNA complex. In vivo, experiments demonstrated that Q12 exhibited a higher tumor growth inhibition rate (TGI) compared to the positive control drug Lenvatinib, while maintaining good safety. In summary, it suggests that Topo I might be a potential target for matrine and Q12 represents a promising candidate for cancer treatment.

Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy.

TOPOI inhibitors have long been a focal point in the research and development of antitumor drugs. PARP-1 plays a crucial role in repairing DNA damage induced by TOPOI inhibitors. Thus, concurrent inhibition of TOPOI and PARP-1 has the potential to augment drug activity. Matrine, characterized by low toxicity and good water solubility, offers advantageous properties. In this investigation, a series of benzimidazole matrine derivatives were designed and synthesized using matrine as the lead compound with the aim of developing dual inhibitors targeting both TOPOI and PARP-1. Among these derivatives, Compound B6 exhibited potent inhibitory effects on PARP-1 and TOPOI, effectively suppressing cancer cell proliferation and migration. Mechanistic assessments revealed that B6 induced DNA damage in HGC-27 cells, leading to G0/G1 cell cycle arrest and significant apoptosis. Molecular docking experiments demonstrated that B6 can effectively enter the active pocket of target proteins, where it forms stable hydrogen bonds with amino acid residues. In vivo, experiments demonstrated that B6 exhibited antitumor activity comparable to that of the positive control drug. The tumor growth inhibition rates (TGIs) for irinotecan, B6 and matrine were 87.0%, 75.4% and 9.7%, respectively. Importantly, B6 demonstrated lower toxicity than the positive control drug. Our findings suggest that TOPOI and PARP-1 may represent potential targets for matrine and B6 emerges as a promising candidate for cancer therapy.

Early vascular changes after silicone oil removal using optical coherence tomography angiography.

BACKGROUND: This study evaluated the vascular changes in the macular and peripapillary regions before and after silicone oil (SO) removal in patients with rhegmatogenous retinal detachment. METHODS: This single-center case series assessed patients who underwent SO removal at one hospital. Patients who underwent pars plana vitrectomy and perfluoropropane gas tamponade (PPV + C3F8) were selected as controls. Superficial vessel density (SVD) and superficial perfusion density (SPD) in the macular and peripapillary regions were assessed by optical coherence tomography angiography (OCTA). Best-corrected visual acuity (BCVA) was assessed using LogMAR. RESULTS: Fifty eyes were administered SO tamponade, 54 SO tamponade(SOT) contralateral eyes, 29 PPV + C3F8 eyes, and 27 PPV + C3F8 contralateral eyes were selected. SVD and SPD in the macular region were lower in eyes administered SO tamponade compared with SOT contralateral eyes (P < 0.01). Except for the central area, SVD and SPD in the other areas of the peripapillary region were reduced after SO tamponade without SO removal (P < 0.01). No significant differences were found in SVD and SPD between PPV + C3F8 contralateral and PPV + C3F8 eyes. After SO removal, macular SVD and SPD showed significant improvements compared with preoperative values, but no improvements in SVD and SPD were observed in the peripapillary region. BCVA (LogMAR) decreased post-operation and was negatively correlated with macular SVD and SPD. CONCLUSIONS: SVD and SPD are decreased during SO tamponade and increased in the macular region of eyes that underwent SO removal, suggesting a possible mechanism for reduced visual acuity during or after SO tamponade. TRIAL REGISTRATION: Registration date: 22/05/2019; Registration number, ChiCTR1900023322; Registration site, Chinese Clinical Trial Registry (ChiCTR).

Different lens power calculation formulas for the prediction of refractive outcome after phacoemulsification with silicone oil removal.

BACKGROUND: Formulas predicting intraocular lens power have not been compared in silicone oil-tamponaded eyes. The study aims to compare six intraocular lens power assessment formulas in silicone oil-tamponaded eyes. METHODS: This prospective study included patients with silicone oil-tamponaded eyes scheduled for silicone oil removal, phacoemulsification, and intraocular lens implantation at Chongqing Aier Eye Hospital (June 2019 to December 2019). Implanted intraocular lens power was used to predict postsurgical spherical equivalence using SRK/T, Holladay 1, Holladay 2, Haigis, Hoffer Q, and Barrett Universal II, and assess those formula's predictive accuracy with predictive error. RESULTS: The analysis included 47 eyes in 47 patients (28 and 19 eyes with normal and long axial length, respectively). Postoperative spherical equivalence at 6 months in normal and long axial length eyes was - 0.6 ± 0.96 and - 0.8 ± 1.52 D, respectively. Predictive error values for SRK/T, Holladay 1, Holladay 2, Haigis, and Hoffer Q and Barrett Universal II were - 0.18 ± 0.92, - 0.15 ± 0.88, - 0.06 ± 0.94, - 0.15 ± 0.87, and - 0.05 ± 0.90 D and - 0.06 ± 0.90, respectively, for normal axial length eyes and 0.15 ± 1.16, 0.46 ± 1.17, 0.28 ± 1.11, - 0.04 ± 1.12, 0.49 ± 1.09 D and 0.11 ± 0.99, respectively, for long axial length eyes. For normal axial length eyes, predicted outcomes were similar to actual outcomes for all formulas. For long axial length eyes, predicted outcomes differed significantly from measured postsurgical values for Holladay 1, Holladay 2, and Hoffer Q (P < 0.05) but not SRK/T or Haigis or Barrett Universal II . CONCLUSIONS: The formulas had comparable predictive accuracy in silicone oil-tamponaded eyes with normal axial length, but Haigis or SRK/T or Barrett Universal II may be preferable in long axial length eyes. TRIAL REGISTRATION: ChiCTR1900023215.

Metabolic Understanding of the Genetic Dysregulation in the Tumor Microenvironment of Kidney Renal Clear Cell Carcinoma.

The metabolic dysregulation is a hallmark of cancers including KIRC, specifically caused by alterations in metabolic genes. Currently, a lack of consensus exists between metabolic signatures in the tumor microenvironment. Here, in this study, we observed the significant correlations of differentially expressed metabolic genes (DEmGs) between KIRC and the related normal samples. Briefly, we collected sets of metabolic genes through RNA-seq data of KIRC and normal tissues from TCGA, followed by the identification of KIRC-related DEmGs. Next, patients were classified into three clusters, and using WGCNA, we identified metabolic genes involved in the survival among different clusters. Furthermore, we investigated survival and clinical parameters along with immune infiltration in the clusters. At the same time, we constructed and validated a prediction model based on these DEmGs. These analyses revealed that the patients having high expression of DEmGs showed poor survival, while infiltration of less-immune cells was associated with the metastasis of KIRC. In the end, we identified NUDT1 as a hub gene as it showed significantly high expression in KIRC samples as well as associated with the survival and prognosis of the patients. Further analysis revealed the oncogenic role of NUDT1 in 786-O and ACHN cells. Thus, we conclude that NUDT1 could be a potential diagnostic and prognostic marker for KIRC.

HNRNPA1-mediated exosomal sorting of miR-483-5p out of renal tubular epithelial cells promotes the progression of diabetic nephropathy-induced renal interstitial fibrosis.

Diabetic nephropathy (DN) is a serious complication in type 1 and type 2 diabetes, and renal interstitial fibrosis plays a key role in DN progression. Here, we aimed to probe into the role and potential mechanism of miR-483-5p in DN-induced renal interstitial fibrosis. In this study, we corroborated that miR-483-5p expression was lessened in type 1 and type 2 diabetic mice kidney tissues and high glucose (HG)-stimulated tubular epithelial cells (TECs), and raised in the exosomes derived from renal tissues in type 1 and type 2 diabetic mice. miR-483-5p restrained the expressions of fibrosis-related genes in vitro and renal interstitial fibrosis in vivo. Mechanistically, miR-483-5p bound both TIMP2 and MAPK1, and TIMP2 and MAPK1 were bound up with the regulation of miR-483-5p on renal TECs under HG conditions. Importantly, HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine. Our results expounded that HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine, thus lessening the restraint of cellular miR-483-5p on MAPK1 and TIMP2 mRNAs, and ultimately boosting extracellular matrix deposition and the progression of DN-induced renal interstitial fibrosis.