Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20.

BACKGROUND: The repurposing of FDA-approved drugs for anti-cancer therapies is appealing due to their established safety profiles and pharmacokinetic properties and can be quickly moved into clinical trials. Cancer progression and resistance to conventional chemotherapy remain the key hurdles in improving the clinical management of colon cancer patients and associated mortality. METHODS: High-throughput screening (HTS) was performed using an annotated library of 1,600 FDA-approved drugs to identify drugs with strong anti-CRC properties. The candidate drug exhibiting most promising inhibitory effects in in-vitro studies was tested for its efficacy using in-vivo models of CRC progression and chemoresistance and patient derived organoids (PTDOs). RESULTS: Albendazole, an anti-helminth drug, demonstrated the strongest inhibitory effects on the tumorigenic potentials of CRC cells, xenograft tumor growth and organoids from mice. Also, albendazole sensitized the chemoresistant CRC cells to 5-fluorouracil (5-FU) and oxaliplatin suggesting potential to treat chemoresistant CRC. Mechanistically, Albendazole treatment modulated the expression of RNF20, to promote apoptosis in CRC cells by delaying the G2/M phase and suppressing anti-apoptotic-Bcl2 family transcription. CONCLUSIONS: Albendazole, an FDA approved drug, carries strong therapeutic potential to treat colon cancers which are aggressive and potentially resistant to conventional chemotherapeutic agents. Our findings also lay the groundwork for further clinical testing.

IL-22 regulates MASTL expression in intestinal epithelial cells.

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation.NEW & NOTEWORTHY MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.

Assessment of phytochemicals, antioxidant, anti-hemolytic, anti-inflammatory and anti-cancer potential of flowers, leaves and stem extracts of.

OBJECTIVE: To evaluate phytochemicals and in vitro biological potential of flowers, leaves and stem extracts of Rosa arvensis. METHODS: Presence of twenty secondary metabolites was confirmed and then phenolic and flavonoid contents were quantified spectrophotometrically. Fourier Transform Infrared spectroscopy was conducted to ascertain functional groups and antioxidant potential was examined using 2,2-diphenyl-1-picrylhydrazyl scavenging activity, total antioxidant capacity and total reducing power assays. Human erythrocytes were used to assess anti-hemolytic activity and five bacterial strains were examined to determine antibacterial potential of plant extracts. Radish seeds were used to perform phytotoxic activity and cytotoxic potential was evaluated via brine shrimps and PC3 cell lines. RESULTS: Highest phenolic contents were detected in the methanolic extract of Rosa arvensis flower (RAFM) [(151.635 ± 0.005) gallic acid equivalent mg/g] and highest flavonoid contents in the chloroform leaf extract (RALC) [(108.228 ± 0.004) quercetin equivalent mg/g]. Fourier-transform infrared spectroscopy analysis showed the presence of wide range of functional groups. The antioxidant assays indicated highest DPPH scavenging activity [IC50 (23.5 ± 0.6) µg/mL] in the methanolic stem extract (RASM), highest total antioxidant capacity [(265.1 ± 0.9) µg/mL] in RAFM and highest reducing potential [(209.9 ± 0.6) µg/mL] in leaf extract (RALM). Highest anti-hemolytic activity [(90.0 ± 0.5) µg/mL] was recorded in RAFM and brine shrimp cytotoxicity potential [(52.3 ± 0.3) µg/mL] in RASM. The antimicrobial activity was detected highest [(21.1 ± 0.5) mm inhibition zones] in RALM against Streptococcus aureus. In the end, anti-inflammatory and anti-cancer activity results depicted less than 50 % inhibition in the methanolic extracts. CONCLUSIONS: Our findings will be helpful in designing pharmaceutical regimens and therefore, more studies can be recommended to isolate and characterize compounds associated with the biological activities of Rosa arvensis.

Characterization, anti-microbial, anti-oxidant and growth promoting effects of biogenically synthesized silver nanoparticles derived from Dicliptera bupleuroides Nees.

One of the most important areas of nanotechnology is the use of nanoparticles (NPs) for a variety of environmental and biological applications, with silver nanoparticles (Ag-NPs) gaining a lot attention due to their distinct properties. The current study deals with the synthesis of Ag-NPs from Dicliptera bupleuroides Nees leaf extract and to determine their antioxidant, antimicrobial potential and effects on wheat seed germination and growth. UV-Visible spectrum revealed a prominent absorption peak at 442 nm, elucidating the conformation of the Ag-NPs synthesis. Scanning electron microscopy (SEM) showed distinctive triangular, pyramidal, and irregular shape. X-ray diffraction (XRD) demonstrated their crystalline nature, with average crystallite size of the Ag-NPs measured at 20.52 nm. Fourier-transform infrared spectroscopy (FT-IR) further confirmed the presence of functional groups such as Phenols (O-H stretch), transition metal carbonyls N-H, ≡C-H, C ≡ N, C ≡ C, C-Cl, C-Br and O-H bonds on the surface Ag-NPs. The antibacterial activity of the Ag-NPs was most pronounced against Bacillus subtilis, with a zone of inhibition (ZOI) measuring 11 mm ± 0.57 at a concentration of 1000 µg/mL (45% inhibition). Likewise, Ag-NPs exhibited highest antioxidant potential (73.2%) at 100 µg/mL compared with standard (ascorbic acid) which showed (76%) at the same concentration. Furthermore, the effect of D. bupleuroides mediated Ag-NPs on wheat seeds growth and germination was recorded maximum at high concentrations (200-300 ppm). In conclusion, D. bupleuroides mediated Ag-NPs showed safe, cost effective and environmentally friendly synthesis which can be used as an antibacterial and antioxidant agent as well as for enhancing the growth and seed germination of crop seeds globally. RESEARCH HIGHLIGHTS: Nanotechnology is the study of nanoparticles for biological and environmental applications. Ag-NPs among other NPs have received broad attention because of their unique properties. D. bupleuroides Ag-NPs: 45% antibacterial, 73.2% antioxidant, enhance wheat germination. D. bupleuroides-mediated Ag-NPs are both cost-effective and environmentally beneficial.

Green solvent-based extraction of three Fabaceae species: A potential antioxidant, anti-diabetic, and anti-leishmanial agents.

The Fabaceae is renowned for its diverse range of chemical compounds with significant biological activities, making it a valuable subject for pharmacological studies. The chemical composition and biological activities of three Fabaceae species were investigated using methanol separately and in combination with dimethyl sulfoxide (DMSO) and glycerol for extraction. The results revealed the highest phenolic (49.59 ± 0.38 mg gallic acid equivalent/g), flavonoid (29.16 ± 0.39 mg rutin equivalent/g), and alkaloid (14.23 ± 0.54 mg atropine equivalent/g) contents in the Caesalpinia decapetala methanol extracts. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and DNA protection activity were the highest (0.88 ± 0.43 µg/mL IC50 and 2149.26 band intensity) in Albizia julibrissin methanol extracts. The α-amylase activity was highest in all methanol extracts (<15 µg/mL IC50 values), while the α-glucosidase inhibition potential was highest (<1 µg/mL IC50 value) in the methanol-glycerol and methanol-DMSO extracts. Pearson coefficient analysis showed a strong positive correlation between the DPPH and α-amylase assays and phytochemicals. Anti-leishmanial activity was observed in decreasing order: A. julibrissin (74.75 %) > C. decapetala (70.86 %) > Indigofera atropurpurea (65.34 %). Gas chromatography-mass spectrometry revealed 33 volatile compounds and, aamong these (Z)-9-octadecenamide was detected in the highest concentration ranging from 21.85 to 38.61 %. Only the methanol extracts of the examined species could be assessed for in vivo studies for immediate applications.