Abstract Background Pancreatic cancer remains one of the most rapidly progressive and deadly malignancies worldwide. Current treatment regimens only result in small improvements overall survival for patients with this type. CPI-613 (Devimistat), a novel lipoate analog inhibiting mitochondrial metabolism, shows new hope pancreatic as an efficient well-tolerated therapeutic option treated alone or combination chemotherapy. Methods cells growing planar 2D cultures 3D scaffold were used research...

Fluorescent transcriptional reporters are widely used as signaling and biomarkers to monitor pathway activities determine cell type identities. However, a large amount of dynamic information is lost due the long half-life fluorescent proteins. To better detect dynamics, can be destabilized shorten their half-lives. applications this approach in vivo limited significant reduction signal intensities. overcome limitation, we enhanced translation protein demonstrate advantages by characterizing...

Significance Direct cell–cell contacts are critical to diverse biological processes in multicellular organisms, including stem cell differentiation, tissue morphogenesis, neurotransmission, tumorigenesis, and immunological responses. However, identifying interacting cells vivo is still a challenging task complex tissues. Here, we introduce new genetic tool, synthetic Notch receptor (synNQ), for efficient visualization manipulation of neighboring vivo. This tool functional most fly tissues...

Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory remains unclear. Here, we showed that compound 6d is an inhibitor Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis mitochondria. Regarding mechanism, identified HDAC6 as direct substrate for 3, and 3 activation induced directly cleaves into two fragments. Moreover, cleavage...

Mitochondria, as the powerhouse of most cells, are not only responsible for generation adenosine triphosphate (ATP) but also play a decisive role in regulation apoptotic cell death, especially cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy urgently required. In this study, effective pancreatic therapy, novel mitochondria-targeted and ROS-triggered drug nanoplatform was developed from TPP-TK-CPI-613 (TTCI) prodrug, ROS-cleave thioketal functions...

For patients exhibiting non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, tyrosine kinase inhibitors (EGFR-TKIs) are a first-line treatment. However, most who initially responded to EGFR-TKIs eventually developed acquired resistance, limiting the effectiveness of therapy. It has long been known that epithelial-mesenchymal transition (EMT) leads resistance in NSCLC. mechanisms underlying dependent on EMT unknown. This research aimed reveal...

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cycle arrest PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cells what is exact molecular mechanism for its antiproliferation effect remained be determined. In present study, exhibited strong suppressing growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression upregulated p27, then...

Abstract Background Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour T-96 human Prostate (CaP) cells and possible underlying mechanisms have not well studied. Results In current study, exerted significant cytotoxicity CaP in vitro induced cell cycle arrest at S-phase dose-dependent...

Abstract Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether a cause or consequence AD. We have previously expressed full‐length human APP Drosophila and established fly AD model that exhibits multiple AD‐like symptoms. Here we report depletion CHIP effectively palliated APP‐induced pathological symptoms, including morphological, behavioral, cognitive defects. Mechanistically, required for...

Background: Breast cancer exhibits poor prognosis and high relapse rates following chemotherapy therapeutics. Thus, this study aims to develop effective novel agents regulating the core molecular pathway of breast such as Wnt/β-catenin signaling. Methods: The present screened a inhibitor, called “C188”, using MTT assay. formula C188 is C 21 H 15 FN 4 O 3 weight 390. Flow cytometry Western blotting were employed assess cell cycle arrest after treatment with C188. Wound-healing transwell...

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) were formed together, accompanied by chromone ring-opening in adducts, under basic conditions without any metal catalyst whole process. Screening data several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 μM). Taken our findings...

Abstract A transition‐metal free, high yielding and efficient three‐component reaction was designed incorporated into two sequential oxidation cyclization cascades in one‐pot with the assistance of microwave irradiation. chemical collection functionalized 3‐substituted imidazopyridines prepared by means mild simple operational procedure. The has a broad tolerance for variety substituted carbonyl aldehydes, anilines 2‐phenyl‐imidazo[1,2‐ ]pyridines. Screening several cancer cell lines...

falafel ( flfl ) encodes a Drosophila homolog of human SMEK whose in vivo functions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis identified as negative regulator JNK pathway-mediated cell death. While ectopic expression suppresses TNF-triggered JNK-dependent death, loss promotes activation death the developing eye wing. These data report for first time an essential physiological function maintaining tissue homeostasis organ development. As...

Abstract Objectives The evolutionary conserved JNK pathway plays crucial role in cell death, yet factors that modulate this signalling have not been fully disclosed. In study, we aim to identify additional regulate and characterize the underlying mechanisms. Materials Methods Drosophila were raised on standard media, cross was carried out at 25°C. Gal4/UAS system used express proteins or RNAi a specific temporal spatial pattern. Gene expression revealed by GFP fluorescence, X‐gal staining...

Cancer remains a major clinical challenge because of the lack effective drug for its treatment. To find out novel cancer chemotherapeutic molecules, we explored anticancer effect imidazopyridine compound 9i and also investigated underlying molecular mechanism.Human cervical cell (HeLa) viability was measured by an MTT assay after treatment with 9i. Clonogenicity HeLa cells in vitro colony formation assay. Cell death visualized propidium iodide (PI) staining. Fluorescence-activated sorting...

Colorectal cancer (CRC) is one of the most common causes cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series previously synthesized imidazolidin-4-one derivatives study their anticancer role in several cell lines. Among these compounds, compound 9r exhibited best activity lines HCT116 SW620. We further investigated molecular mechanism 9r. found that induced mitochondrial pathway apoptosis SW620 cells...

TosMIC causes ring expansion of p -QMs: highly substituted pyrrolotropones are rapidly assembled in a domino process mediated by DBU. The utility the method was highlighted follow-up transformation and biological activity identification.

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor by the generation of excessive highly cytotoxic ROS. However, poor water solubility photosensitizer, reactive oxygen species (ROS) depleting high concentrations glutathione (GSH) in tumor microenvironment and activation DNA repair pathways to combat oxidative damage, will significantly limit effect PDT. Herein, we developed a photosensitizer prodrug (CSP) conjugating...

In this study, 2-benzyl-10a-(1H-pyrrol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-1,4,10(10aH)-trione (DHPITO), a previously identified inhibitor against hepatocellular carcinoma cells, is shown to exert its cytotoxic effects by suppressing the proliferation and growth of CRC cells. An investigation molecular mechanism confirmed that activity DHPITO mediated through targeting microtubules with promotion subsequent microtubule polymerisation. With microtubule-stabilising ability, also...