HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma.

Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, excluding ccRCC.

Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Unlabelled: Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis.

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC.

Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer.

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CBR) Receptor with Reduced Lipophilicity.

In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CBR). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CBR and potent CBR antagonist activities.

The key role of NLRP3 and STING in APOL1-associated podocytopathy.

Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels.

CB R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1 ). We found overexpression of CB R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice.

Functional Selectivity of a Biased Cannabinoid-1 Receptor (CBR) Antagonist.

Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CBR antagonist (MRI-1891) highly biased toward inhibiting CBR-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CBR occupancy.

The Heterogeneity of Lipid Metabolism in Cancer.

The study of cancer cell metabolism has traditionally focused on glycolysis and glutaminolysis. However, lipidomic technologies have matured considerably over the last decade and broadened our understanding of how lipid metabolism is relevant to cancer biology [1-3]. Studies now suggest that the reprogramming of cellular lipid metabolism contributes directly to malignant transformation and progression [4, 5].

Cholesterol as a modulator of cannabinoid receptor CB signaling.

Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB, we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzo[d]thiazol-3(2H)-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes.

Bleomycin Induces Drug Efflux in Lungs. A Pitfall for Pharmacological Studies of Pulmonary Fibrosis.

ATP-binding cassette (ABC) transporters are evolutionarily conserved membrane proteins that pump a variety of endogenous substrates across cell membranes. Certain subfamilies are known to interact with pharmaceutical compounds, potentially influencing drug delivery and treatment efficacy. However, the role of drug resistance-associated ABC transporters has not been examined in idiopathic pulmonary fibrosis (IPF) or its animal model: the bleomycin (BLM)-induced murine model.

Targeting Peripheral CB Receptors Reduces Ethanol Intake via a Gut-Brain Axis.

Endocannabinoids acting on the cannabinoid-1 receptor (CBR) or ghrelin acting on its receptor (GHS-R) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CBR inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CBR, ghrelin peptide or GHS-R. JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin.

Crystal Structure of the Human Cannabinoid Receptor CB2.

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution.

The Heterogeneity of Lipid Metabolism in Cancer.

The study of cancer cell metabolism has traditionally focused on glycolysis and glutaminolysis. However, lipidomic technologies have matured considerably over the last decade and broadened our understanding of how lipid metabolism is relevant to cancer biology [1–3]. Studies now suggest that the reprogramming of cellular lipid metabolism contributes directly to malignant transformation and progression [4, 5].

Synthesis of C -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB R) and inducible nitric oxide synthase (iNOS).

Cannabinoid-1 receptor (CB R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis. Cannabinoid-1 receptor inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models. Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders.

A qualitative study examining methods of accessing and identifying research relevant to clinical practice among rehabilitation clinicians.

Purpose: Research examining the utilization of evidence-based practice (EBP) specifically among rehabilitation clinicians is limited. The objective of this study was to examine how various rehabilitative clinicians including physical therapists, occupational therapists, rehabilitation counselors, and physiatrists are gaining access to literature and whether they are able to implement the available research into practice.

Methods: A total of 21 total clinicians were interviewed via telephone.

Decreasing CB receptor signaling in Kupffer cells improves insulin sensitivity in obese mice.

Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CBR has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance.

Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy.

Aims: To determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB R) in the development of diabetic nephropathy (DN), relative to CB R in other renal cell types.

Material And Methods: We developed a mouse model with a podocyte-specific deletion of CB R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB R activation.

Identifying and Understanding the Health Information Experiences and Preferences of Individuals With TBI, SCI, and Burn Injuries.

Introduction: Traumatic brain injury, spinal cord injury, and burn injury can cause lifelong disability and changes in quality of life. In order to meet the challenges of postinjury life, various types of health information are needed. We sought to identify preferred sources of health information and services for persons with these injuries and discover how accessibility could be improved.

Synthesis of S-2-((S)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamido)-3-(methyl-d )butanamide-d , octadeuterated JD5037.

JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB R) receptor. Peripheral CB receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated [ H ]-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d starting material.

Identifying and Understanding the Health Information Experiences and Preferences of Caregivers of Individuals With Either Traumatic Brain Injury, Spinal Cord Injury, or Burn Injury: A Qualitative Investigation.

Background: In order to meet the challenges of caring for an injured person, caregivers need access to health information. However, caregivers often feel that they lack adequate information. Previous studies of caregivers have primarily focused on either their time and emotional burdens or their health outcomes, but the information needs of caregivers have not been thoroughly investigated.

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy. To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CB1R) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CB1R system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls.

Optimizing Scoring and Sampling Methods for Assessing Built Neighborhood Environment Quality in Residential Areas.

Optimization of existing measurement tools is necessary to explore links between aspects of the neighborhood built environment and health behaviors or outcomes. We evaluate a scoring method for virtual neighborhood audits utilizing the Active Neighborhood Checklist (the Checklist), a neighborhood audit measure, and assess street segment representativeness in low-income neighborhoods. Eighty-two home neighborhoods of Washington, D.

Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CBR Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis.

We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CBR) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB receptor (CBR) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CBR antagonist activities and iNOS inhibitory activities.

Ephrin-A3 promotes and maintains slow muscle fiber identity during postnatal development and reinnervation.

Each adult mammalian skeletal muscle has a unique complement of fast and slow myofibers, reflecting patterns established during development and reinforced via their innervation by fast and slow motor neurons. Existing data support a model of postnatal "matching" whereby predetermined myofiber type identity promotes pruning of inappropriate motor axons, but no molecular mechanism has yet been identified. We present evidence that fiber type-specific repulsive interactions inhibit innervation of slow myofibers by fast motor axons during both postnatal maturation of the neuromuscular junction and myofiber reinnervation after injury.