Structure-Activity Relationship Study of (E)-3-(6-Fluoro-1H-indol-3-Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) Against Metastatic Colorectal Cancers Resistant to Oxaliplatin.

Advanced metastatic colorectal cancer (mCRC) and the development of drug resistance to chemotherapy pose significant challenges in clinical settings. In previous studies, we have demonstrated the potent cytotoxic activity of (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) and related 30 derivatives against mCRC by targeting microtubules. In this study, we aimed to evaluate the efficacy of the 31 compounds and explore the structure-activity relationship (SAR) against oxaliplatin-resistant mCRC. We found that most of the derivatives showed high sensitivity toward the oxaliplatin-resistant HCT-116/L cells. Particularly, FC116 exhibited a better GI50 value against the resistant mCRC cell line, HCT-116/L, compared to standard therapies. We also observed a safer therapeutic window for FC116 and a synergistic effect when it was used in combination with oxaliplatin. Mechanistically, FC116 induced the G2/M phase arrest by downregulating cyclin B1 expression through its interaction with microtubules in resistant colorectal cancer cells. Furthermore, in vivo experiments demonstrated that FC116 significantly suppressed tumor growth, achieving a 78% reduction at a dose of 3 mg/kg, which was superior to the 40% reduction achieved by oxaliplatin treatment. Overall, our findings suggest that the indole-chalcone compound FC116 represents a promising lead for chemotherapy in oxaliplatin-resistant mCRC.

Sex-Biased Gene Expression of Mesobuthus martensii Collected from Gansu Province, China, Reveals Their Different Therapeutic Potentials.

The scorpions, named Mesobuthus martensii, commonly called Quanxie () in Chinese, have been widely used as one of the animal medicines for more than 1,000 years because of the strong toxicity of their venoms. Meanwhile, scorpions are sexually dimorphic in appearance, and many exhibit traits associated with sex-biased gene expression, including maternal care, mating competition, female mating choices, ecology, and even venom composition and lethality. This study aims to explore the differences in composition of the venom of scorpions of different sex using the method of transcriptomics. Whole de novo transcriptomes were performed on the samples of M. martensii captured from Gansu Province to identify their sex-biased gene expression. The conserved CO-1 sequences of the captured samples matched that of M. martensii. A total of 8,444 (35.15%), 7,636 (31.78%), 8,510 (35.42%), 7,840 (32.63%), 9,980 (41.54%), and 11,829 (49.23%) unigenes were annotated with GO, KEGG, Pfam, Swissprot, eggNOG, and NR databases. Moreover, a total of 43 metalloproteases, 40 potassium channel toxins, 24 phospholipases, 12 defensins, 10 peroxiredoxins, 9 cysteine proteinase inhibitors, 7 serine protease inhibitors, 6 sodium channel toxins, 2 NDBPs, 1 calcium channel toxin, 1 waprin-like peptide, 1 antibacterial peptide, 1 antimicrobial peptide, and 1 anticoagulant peptide were screened out. With the fold change of 2 and 0.5, p value < 0.01, and q value < 0.05 as thresholds, a total of 41 out of 157 (26.11%) toxin-related unigenes had significant differential expression, and this ratio was much higher than the ratio of differentially expressed unigenes out of all annotated ones (8.84%). Of these differentially expressed toxins, 28 were upregulated and occupied the majority, up to 68.30%. The female scorpions showed more upregulated unigenes that annotated with toxins and had the potential to be used as more effective therapeutic drugs. In addition, this method of omics can be further used as a useful way to identify the difference between female and male toxic animals.

Clinical significance and mechanism of LncRNA GAS-5 in osteoarthritis.

OBJECTIVE: To investigate the clinical significance and mechanism of LncRNA GAS-5 in osteoarthritis. METHODS: 67 patients with knee osteoarthritis (the case group) and 60 patients who underwent physical examination (the healthy group) were selected to evaluate the expression level of lncRNA GAS-5 in peripheral blood mononuclear cells. Cell experiments were conducted that took THP-1 cells carrying NC-shRNA (negative lentivirus) as the control group, and THP1 cells carrying GAS5-shRNA (lentivirus infection) as the study group; we evaluated the expression of lncRNA GAS-5 gene, and the expression of immune-related cytokines. RESULTS: (1) The expression of lncRNA GAS-5 in the case group was lower than in the healthy group (P<0.05). (2) The expression level of lncRNA GAS-5 in the case group versus control group, had an inhibition rate of 65.49% (P<0.05). The expression levels of 18 cytokines such as IL-1, IL-2, IL-6, IL-7, IL-17, G-CSF, M-CSF, and TGF-ß1, in the study group were higher than in the control group (P<0.05), but the expression of IL-10 and IL-13 were significantly lower than in the control group (P<0.05). CONCLUSION: The expression of lncRNA GAS-5 is low in osteoarthritis patients. While the expression of lncRNA GAS-5 is inhibited, related immune and inflammatory factors are also affected, so lncRNA GAS-5 may affect the occurrence and progression of osteoarthritis through immune regulation. A low level of lncRNA GAS-5 may be a marker for the occurrence and progression of osteoarthritis.

Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury.

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good KD2 value of 0.455 µM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.

Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors.

Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.

Diffusion-weighted magnetic resonance imaging in bladder cancer: comparison of readout-segmented and single-shot EPI techniques.

BACKGROUND: To evaluate whether readout-segment echo-planar imaging (RS-EPI) can provide better image quality in assessing bladder cancer than single-shot echo-planar imaging (SS-EPI) and to compare quantitative imaging parameters derived from both techniques. METHODS: Seventy patients with bladder lesions were enrolled and underwent diffusion-weighted imaging on a 3 Tesla magnetic resonance scanner using axial RS-EPI and SS-EPI techniques. Two observers independently assessed the susceptibility, detectability, motion artefacts and blurring of the images using qualitative scores. The signal-to-noise ratio (SNR), signal intensity ratio (SIR), contrast-to-noise ratio (CNR) and ADC values of the bladder lesions were measured and compared between the two techniques and between two observers. Qualitative and quantitative comparisons of image quality were performed using the Wilcoxon signed-rank test and paired t-test. In addition, the agreement of the ADC measurements was evaluated using ICC values and Bland-Altman plots. RESULTS: Sixty-eight patients were included in the final analysis. The scores of image susceptibility, detectability and blurring for RS-EPI were significantly higher than those for SS-EPI (all p < 0.05), while the motion artefact was not. There were significant differences between RS-EPI and SS-EPI in the CNR and SIR values (all p < 0.05) but not in the SNR or ADC values (all p > 0.05). The ICC values and Bland-Altman plots also showed excellent agreement between the measured ADC values of the bladder lesions. CONCLUSIONS: The RS-EPI technique provides significantly better image quality in patients with bladder cancer than the SS-EPI technique, without a significant difference in the ADC value.