Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.

In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 (SREBP-2) pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, new strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport.

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis.

PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.

Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P.

PIP kinases: A versatile family that demands further therapeutic attention.

Phosphoinositides are membrane-localized phospholipids that regulate a plethora of essential cellular processes. These lipid signaling molecules are critical for cell homeostasis and therefore their levels are strictly regulated by the coordinated action of several families of lipid kinases and phosphatases. In this review, we provide a focused perspective on the phosphatidylinositol phosphate kinase (PIPK) family and the three subfamilies that compose it: Type I PIPKs or phosphatidylinositol-4-phosphate 5-kinases (PI4P5Ks), Type II PIPKs or phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks), and Type III PIPKs or phosphatidylinositol-3-phosphate 5-kinases (PIKfyve).

Expanding role of PI5P4Ks in cancer: A promising druggable target.

Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are a family of druggable stress-regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies.

JAK Inhibitors Suppress Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice.

Background: Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitory factor (LIF) which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues.

Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.

Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry.

Temporal control of bidirectional lipid-droplet motion in Drosophila depends on the ratio of kinesin-1 and its co-factor Halo.

During bidirectional transport, individual cargoes move continuously back and forth along microtubule tracks, yet the cargo population overall displays directed net transport. How such transport is controlled temporally is not well understood. We analyzed this issue for bidirectionally moving lipid droplets in Drosophila embryos, a system in which net transport direction is developmentally controlled.

Ocimum Sanctum seeds, a natural superdisintegrant: formulation and evaluation of fast melt tablets of nimesulide.

Background: Fast melt tablets, also known as fast dissolving tablets, disintegrate instantaneously within the mouth and thus can be consumed without water. The present study was aimed to formulate fast melt tablets of nimesulide by using Ocimum Sanctum seeds as a natural tablet superdisintegrant.

Material And Methods: Powdered Ocimum seeds were characterized for powder flow properties (bulk density, tapped density, Carr's consolidation index, Hausner ratio, angle of repose), swelling index, viscosity, pH, loss on drying and microbial load.

Current clinical coverage of Radiation Therapy Oncology Group-defined target volumes for postmastectomy radiation therapy.

Purpose: The Radiation Therapy Oncology Group (RTOG) has published consensus guidelines for contouring relevant anatomy for postmastectomy radiation therapy (RT). How these contours relate to current treatment practices is unknown. We analyzed the dose-volume histograms (DVHs) for these contours using current clinical practice at University of Texas MD Anderson Cancer Center and compared them with the proposed treatment plans to treat RTOG-defined targets to full dose.

Formulation and evaluation of controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum.

The aim of study was to prepare controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum as natural polymer. Tablets were formulated by direct compression technology employing the natural polymer in different concentrations (5, 10, 15 and 20% w/w). The prepared batches were evaluated for drug assay, diameter, thickness, hardness and tensile strength, swelling index, mucoadhesive strength (using texture analyzer) and subjected to in vitro drug release studies.

Taste masked microspheres of ofloxacin: formulation and evaluation of orodispersible tablets.

Ofloxacin is a synthetic chemotherapeutic antibiotic used for treatment of a variety of bacterial infections, but therapy suffers from low patients' compliance due to its unpleasant taste. This study was aimed to develop taste masked microspheres of ofloxacin using Eudragit and to prepare orodispersible tablets of the formulated microspheres using natural superdisintegrant. Taste masking Eudragit E100 microspheres were prepared by solvent evaporation technique with an entrapment efficiency ranging from 69.

Formulation and evaluation of mucoadhesive matrix tablets of taro gum: optimization using response surface methodology.

The present study was aimed to formulate and evaluate oral controlled release mucoadhesive matrix tablets of taro gum incorporating domperidone as model drug. Tablets were prepared by direct compression and were evaluated for bioadhesive strength and in vitro dissolution parameters. A central composite design for 2 factors, at 3 levels each, was employed to evaluate the effect of criti cal formulation variables, namely the amount of taro gum (X1) and PVP K 30 (X2), on mucoadhesive strength, tensile strength, release exponent (n) and t50 (time for 50% drug release).

Locust bean gum as superdisintegrant--formulation and evaluation of nimesulide orodispersible tablets.

Orodispersible tablets disperse instantaneously in the mouth so that they can be swallowed without the aid of water. The aim of the present study was to formulate nimesulide orodispersible tablets using locust bean gum as a natural superdisintegrant. The gum was evaluated for powder flow properties, swelling index and loss on drying.

Lallemantia reylenne seeds as superdisintegrant: Formulation and evaluation of nimesulide orodispersible tablets.

Aim: Orodispersible tablets also known as fast dissolving tablets disintegrate instantaneously within the mouth and thus can be consumed without water. The present study was aimed to formulate orodispersible tablets of nimesulide by using Lallemantia reylenne seeds as natural superdisintegrant.

Materials And Methods: Powdered lallemantia seeds were characterized for powder flow properties (bulk density, tapped density, carr's consolidation index, hausner ratio, angle of repose), swelling index, viscosity, pH, and loss on drying.