BIM

Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). While inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a pro-apoptotic response...

CONTEXT: BIM (Bcl-2 interacting mediator of apoptosis)-derived peptides that specifically target over-expressed Mcl-1 (myeloid cell leukemia-1) protein and induce apoptosis are potentially anti-cancer agents. Since the helicity of BIM-derived peptides has a crucial role in their functionality, a range of strategies have been used to increase the helicity including the introduction of unnatural residues and stapling methods that have some drawbacks such as the accumulation in the liver...

The study evaluates metal concentrations, distributions, contamination, risk, sources, fractionation, and mobility in Nabq Protectorate sediments, revealing a metal content order of Fe, Mn, Pb, Ni, and Cd. Metals are dominated by residual fractions, with Cd (83.70 %) > Ni (82.98 %) > Pb (80.96 %) > Fe (80.31 %) > Mn (76.65 %) reflecting the natural sources of investigated metals. Mn (23.35 %) was the most abundant mobile metal, and the sediments of the protectorate had low toxicity and moderate risk according to the synergistic indices (1 ≤ mRAC<10 and ERM; 5-10)...

Anguillid eel populations are under threat globally. A particularly vulnerable life-cycle stage is the migration of mature adult eels downstream from freshwater habitats through estuaries into the sea to spawn. This study investigated the factors associated with downstream migration of the short-finned eel Anguilla australis (Richardson 1841) from a coastal wetland (Lake Condah) in south-east Australia, using acoustic telemetry. Migration was associated with time of the year, higher water level and river flows, decreasing water temperature, and darker moon phases...

The effects of climate change and the rapid growth of societies often lead to water scarcity and inadequate water quality, resulting in a significant number of diseases. The digitalization of infrastructure and the use of Digital Twins are presented as alternatives for optimizing resources and the necessary infrastructure in the water cycle. This paper presents a framework for the development of a Digital Twin platform for a wastewater treatment plant, based on a microservices architecture which optimized its design for edge computing implementation...

The process of degrading unwanted or damaged mitochondria by autophagy, called mitophagy, is essential for mitochondrial quality control together with mitochondrial apoptosis. In mammalian cells, pan-Bcl-2 family members including conical Bcl-2 members and non-conical ones are involved in and govern the two processes. We have illustrated recently the BH3 receptor Hsp70 interacts with Bim to mediate both apoptosis and mitophagy. However, whether similar pathways exist in lower eukaryotes where conical Bcl-2 members are absent remained unclear...

GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent...

Metastatic BRAFV600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAFV600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1...

Drug-eluting contact lenses (DECLs) incorporated with poly(lactic-co-glycolic acid) (PLGA) and various model drugs (ketotifen fumarate, bimatoprost and latanoprost) were fabricated using nanoelectrospray (nES) approach. The resulting DECLs demonstrated outstanding optical transmittance within the optical zone, indicating that the employed coating procedure did not compromise visual acuity under the prescribed spraying parameters. In vitro drug release assessments of the model drugs (ketotifen fumarate (KF), bimatoprost (BIM), and latanoprost (LN)) revealed a strong correlation between the model drug's hydrophobicity and the duration of drug release...

Ovarian endometriosis is characterized by the growth of endometrial tissue within the ovary, causing infertility and chronic pain. However, its pathophysiology remains unclear. Utilizing high-precision single-cell RNA sequencing, we profile the normal, eutopic, and ectopic endometrium from 34 individuals across proliferative and secretory phases. We observe an increased proportion of ciliated cells in both eutopic and ectopic endometrium, characterized by a diminished expression of estrogen sulfotransferase, which likely confers apoptosis resistance...

The synthesis of indoles and their derivatives, more specifically bis(indolyl)methanes (BIMs), has been an area of great interest in organic chemistry, since these compounds exhibit a range of interesting biological and pharmacological properties. BIMs are naturally found in cruciferous vegetables and have been shown to be effective antifungal, antibacterial, anti-inflammatory, and even anticancer agents. Traditionally, the synthesis of BIMs has been achieved upon the acidic condensation of an aldehyde with indole, utilizing a variety of protic or Lewis acids...

INTRODUCTION: Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficacy is limited by the development of acquired resistance. METHODS: A specific inhibitor of Hsp70-Bim protein-protein interaction (PPI), S1g-2, together with an inhibitor of Hsp70-Bag3 PPI, MKT-077 and an ATP-competitive inhibitor VER155008, were used as chemical tools...

Age-related macular degeneration (AMD) is a vision threatening disease in older adults. Anti-VEGF treatment is effective for the majority of neovascular AMD (nAMD) patients, although approximately 30% of nAMD patients have an incomplete response for unknown reasons. Here we assessed the contribution of single nucleotide polymorphisms (SNPs) in key angioinflammatory regulatory genes in nAMD patients with an incomplete response compared to those responsive to anti-VEGF treatment. A total of 25 responsive and 30 nAMD patients with an incomplete response to anti-vascular endothelial growth factor (anti-VEGF) treatment were examined for known SNPs that impact the structure and function of thromobospondin-1 (TSP1), Bcl-2-interacting mediator of cell death (BIM) and complement factor H (CFH)...

Dendrobium officinale is an important edible and medicinal plant, with the Dendrobium officinale polysaccharide (DOP) being its primary active constituent, known for its diverse biological activities. In this study, DOP was extracted and characterized for its structural properties. The potential of DOP to ameliorate gastric ulcers (GUs) was investigated using an acetic-acid-induced GU model in rats. The results demonstrated that DOP exerted a multifaceted protective effect against GU, mitigating the deleterious impact on food intake and body weight in rats...

The building sector's significant greenhouse gas emissions and energy consumption present added challenges to meeting European climate commitments amidst rapid population growth. In Luxembourg, single-family houses dominate the residential buildings, noticeably contributing to construction waste and CO2 emissions. This study compares the environmental impacts of a three-story reinforced concrete masonry single-family house and an identical timber building in Luxembourg, emphasizing greenhouse gas emissions and embodied energy...

The importance of construction automation has grown worldwide, aiming to deliver new machineries for the automation of roads, tunnels, bridges, buildings and earth-work construction. This need is mainly driven by (i) the shortage and rising costs of skilled workers, (ii) the tremendous increased needs for new infrastructures to serve the daily activities and (iii) the immense demand for maintenance of ageing infrastructure. Shotcrete (sprayed concrete) is increasingly becoming popular technology among contractors and builders, as its application is extremely economical and flexible as the growth in construction repairs in developed countries demand excessive automation of concrete placement...

To investigate the intrinsic relation between carbonic anhydrase inhibition and anticancer activity, we have prepared four sets of diaryl urea molecules and tested for the inhibition of hCA-IX and XII on two breast cancer cell lines. Among 21 compounds, compound J2 (with -SO2 NH2 group) and J16 (without -SO2 NH2 group) showed the best activity under normoxic and hypoxic conditions. The IC50 values of J16 for MDA-MB-231 and MCF-7 cells, under normoxic condition were 6.3 and 3.7 µM respectively, which are 1...

Transition-metal photoredox catalysis has transformed organic synthesis by harnessing light to construct complex molecules. Nickel(II)-bipyridine (bpy) aryl halide complexes are a significant class of cross-coupling catalysts that can be activated via direct light excitation. This study investigates the effects of molecular structure on the photophysics of these catalysts by considering an underexplored, structurally constrained Ni(II)-bpy aryl halide complex in which the aryl and bpy ligands are covalently tethered alongside traditional unconstrained complexes...

The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML...

Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified...