Kidney diseases represent one of the most prevalent and rapidly growing global health burdens, with rising mortality linked to both acute kidney injury and chronic kidney disease (CKD). Despite the increasing incidence o...Kidney diseases represent one of the most prevalent and rapidly growing global health burdens, with rising mortality linked to both acute kidney injury and chronic kidney disease (CKD). Despite the increasing incidence of CKD affecting 8%-16% of the world's population, therapeutic options remain limited, largely because of an incomplete understanding of underlying pathophysiology and the lack of reliable biomarkers. Recent evidence highlights that free-fatty acids (FFA), particularly short-chain and long-chain fatty acids, are beneficial modulators of renal health, associated with reduced CKD risk and slower kidney function decline. Although effects of FFA have historically been linked to their intracellular activity, they can also engage a family of cell-surface G protein-coupled FFA receptors (FFAR), including FFARs FFA2/GPR43 and FFA3/GPR41, which are activated by short-chain fatty acids, and FFA1/GPR40 and FFA4/GPR120, which are agonized by long-chain fatty acids. This review summarizes current knowledge of FFAR-mediated mechanisms in acute kidney injury, CKD, and associated renal pathologies, emphasizing their potential as therapeutic targets to improve kidney outcomes. We also discuss the therapeutic relevance of dietary FFA related to these FFAR in relation to renal disease. SIGNIFICANCE STATEMENT: Fatty acid sensing G protein-coupled receptors have emerged as important regulators of renal inflammation, fibrosis, and tubular survival across acute and chronic models of kidney injury. This review synthesizes current evidence for short- and long-chain free-fatty acid receptors in kidney disease, highlights translational relevance, and outlines challenges that must be addressed to advance free-fatty acid receptor-targeted therapies.
Previous studies demonstrated that CNS4, a glutamate concentration biased N-methyl-D-aspartate receptor modulator, produces central analgesic and stress mitigating effects in mice. To translate these findings to a nonrod...Previous studies demonstrated that CNS4, a glutamate concentration biased N-methyl-D-aspartate receptor modulator, produces central analgesic and stress mitigating effects in mice. To translate these findings to a nonrodent species, we evaluated the pharmacokinetics (PK) and safety of CNS4 in 21 adult beagle dogs. A custom formulation was developed for subcutaneous (SC) delivery, and an initial 2 dose PK study (5 and 10 mg/kg) was conducted. CNS4 achieved rapid absorption, with T values of 1.50 ± 0.87 hour (5 mg/kg) and 1.67 ± 0.58 hour (10 mg/kg). Pharmacokinetics were comparable across the limited doses studied, and apparent volumes of distribution for the extravascular route were 33.5 ± 12.5 and 25.6 ± 3.67 L/kg, respectively. To assess oral feasibility, a 50 mg/kg dose of CNS4 suspended in 0.5% carboxymethyl cellulose was first tested in mice and then in dogs. Oral administration in dogs resulted in rapid absorption, with a T of ∼1 hour, comparable to the SC route. Systemic tolerability was assessed in an acute toxicity study involving 4 groups (vehicle, 5, 10, and 25 mg/kg SC) of dogs. No changes in behavior, food intake, or body weight were observed over 14 days. Hematology, lipid panels, and electrolyte measurements collected on days 0 (predose), 7, and 14 revealed no significant CNS4 related abnormalities. Together, these findings demonstrate that CNS4 has an acceptable safety profile and predictable PK across SC and oral administration routes in dogs. This first-in-dog evaluation supports further development of CNS4 as a potential non opioid analgesic and stress mitigating therapeutic agent. SIGNIFICANCE STATEMENT: N-methyl-D-aspartate receptor subtypes are attractive therapeutic targets for chronic pain and post-traumatic stress disorder because of their critical role in emotional memory formation. This translational pharmacology study demonstrates the safety and predictable pharmacokinetics of a centrally acting analgesic and stress mitigating N-methyl-D-aspartate receptor modulator (CNS4) in dogs after single dose subcutaneous and oral administration.
Preclinical studies indicate that blocking diacylglycerol kinase (DGK) family members DGKα or DGKζ can improve antitumor immunity, prompting the development of clinical-stage, potent and selective small molecule inhibito...Preclinical studies indicate that blocking diacylglycerol kinase (DGK) family members DGKα or DGKζ can improve antitumor immunity, prompting the development of clinical-stage, potent and selective small molecule inhibitors of DGKα and/or DGKζ. DGKα and DGKζ are the most widely expressed DGK family members by immune cells, and both enzymes convert the signaling lipid diacylglycerol (DAG) to phosphatidic acid. DAG is a critical second messenger downstream of T cell receptor (TCR) stimulation that promotes activation and effector function. Blocking DGKα or DGKζ activity enhances DAG-mediated signaling, potentiating immune cell activity. Because DGKα and DGKζ functionally overlap, we sought to compare the effects of pharmacological inhibition strategies targeting DGKα or DGKζ individually or simultaneously (DGKα/ζ) to determine which approach maximized immune cell activation. Evaluation of TCR downstream signaling using primary human and mouse cells revealed that dual DGKα/ζ inhibition promoted the greatest increase in cellular activity, including antigen-dependent cytokine production and tumor cell killing. In contrast, pharmacological inhibition of DGKζ alone had modest effects, and inhibition of DGKα alone had minimal bearing on TCR-mediated activity. Notably, loss of DGKα and DGKζ protein was observed following inhibitor treatment and may point to an additional mechanism of action for DGK targeting small molecule inhibitors. Finally, analysis of biopsies from patients with nonsmall cell lung cancer showed that tumor infiltrating lymphocytes expressed both DGKα and DGKζ and exhibited increased activation and cytokine production ex vivo upon DGKα/ζ coinhibition in conjunction with TCR stimulation, indicating that tumor infiltrating lymphocytes are sensitive to DGKα/ζ coinhibition. SIGNIFICANCE STATEMENT: This work directly compares pharmacological inhibition of DGKα and DGKζ, affirming that DGKα/ζ coinhibition is required to maximally increase TCR responses. Importantly, DGKα/ζ inhibition increased activation and cytokine production in both healthy T cells and tumor infiltrating lymphocytes.
Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies with only an 11% 5-year survival rate. Oncogenic microRNAs (miRNA), particularly miR-21, miR-155, and miR-18a, drive tumor progression by silen...Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies with only an 11% 5-year survival rate. Oncogenic microRNAs (miRNA), particularly miR-21, miR-155, and miR-18a, drive tumor progression by silencing tumor suppressors and promoting chemoresistance. Single-target miRNA inhibition has shown limited clinical efficacy because of complex network redundancy and compensatory pathway activation, necessitating multitarget therapeutic approaches. We designed and validated a trispecific miRNA sponge construct containing high-affinity target sites for all 3 oncomiRs, demonstrated in silico through miRNAsong analysis with an approximately 11-kcal/mol thermodynamic specificity gap relative to off-targets. The sponge was functionally tested in the human pancreatic ductal adenocarcinoma cell lines PANC-1 and AsPC-1 using comprehensive assays including dual-luciferase reporter, quantitative reverse transcription polymerase chain reaction, flow cytometry-based apoptosis analysis, scratch-wound migration, and gemcitabine chemosensitization studies. In AsPC-1 cells, the trispecific sponge achieved 99.0%-99.9% silencing of target miRNAs and 349-fold reporter reduction, inducing a 6.1-fold increase in apoptosis and approximately 44% reduction in wound closure at 72 hours compared with nontargeting controls. PANC-1 cells showed moderate but significant responses with 65%-98% miRNA silencing, a 2.2-fold increase in apoptosis, and approximately 51% reduction in wound closure at 72 hours under identical assay conditions. Mechanistically, simultaneous miRNA inhibition synergistically reactivated tumor suppressor genes PDCD4, ESR1, and NOTCH2 (6.3-7.7-fold upregulation) and sensitized chemoresistant cells to gemcitabine by 1.5- to 1.8-fold. Across the evaluated functional endpoints, the trispecific sponge conferred approximately 1.2- to 95-fold changes relative to the nontargeting control and, in many instances, elicited equal or greater effects than single-target constructs, consistent with a broader network-level impact rather than uniform superiority in every assay. This platform represents a promising strategy for pancreatic ductal adenocarcinoma therapy warranting preclinical development and clinical translation. SIGNIFICANCE STATEMENT: Pancreatic cancer chemoresistance drives poor survival. The trispecific microRNA sponge simultaneously targets miR-21, miR-155, and miR-18a, synergistically reactivating tumor suppressors and enhancing gemcitabine efficacy more than single-target approaches. This multitarget microRNA strategy represents a novel therapeutic platform for overcoming chemoresistance in pancreatic cancer.
J Pharmacol Exp Ther
· 2026 May · PMID 42019163
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The...Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The absence of molecular targets in TNBC limits treatment options and contributes to increased rates of recurrence, metastasis, and resistance to conventional therapies. TNBC, however, is rich in tumor-infiltrating lymphocytes; hence, elevated programmed death-ligand 1 expression makes these tumors amenable to immunotherapy. A variety of antibodies and immunomodulatory drugs are being explored for TNBC treatment, this review specifically focuses on design of immunomodulatory peptides for TNBC treatment. This review comprehensively discusses the peptide-based approaches for immunomodulating tumor microenvironment (TME) of TNBC and to enhance antitumor immune response. The peptide-mediated modulation of innate immune cells including tumor-associated macrophages, neutrophils, dendritic cells, and natural killer cells, as well as T cells of the adaptive immune system is explored in detail. The applications of peptides as immune checkpoint inhibitors and highlights of emerging strategies that employ peptides to induce immunogenic cell death to stimulate antitumor immunity are discussed. Immunogenic cell death inducing peptides promote the release of immunogenic signals such as damage-associated molecular patterns from dying cancer cells, which further activate dendritic cells, T cells, and neutrophils, thereby reshaping the TME to support robust antitumor immunity. These strategies underscore the transformative potential of peptide therapeutics to harness the immune system and reshape TME, offering a promising avenue for more effective and durable TNBC treatment. SIGNIFICANCE STATEMENT: With growing interest in peptides as tumor microenvironment modulator, this review provides an in-depth analysis of interactions and crosstalk between immune and tumor cells and explores therapeutic potential of peptides in modulating immune cell signaling pathways, with ultimate impact as anticancer agents for triple-negative breast cancer.
Guilding C, Kelly-Laubscher R, Cunningham M
… +9 more, Dilles T, Kennedy D, Brinkman DJ, Eid AH, Quesnelle KM, Engels F, Maxwell S, Christopoulos A, White PJ
Pharmacol Rev
· 2026 May · PMID 42019093
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We are arguably experiencing the greatest disruption to higher education in modern history. High-quality education research has demonstrated that active learning and other innovations are significantly more effective tha...We are arguably experiencing the greatest disruption to higher education in modern history. High-quality education research has demonstrated that active learning and other innovations are significantly more effective than traditional methods. The recent pandemic forced educators to adapt in previously unimaginable ways. Generative artificial intelligence now presents great challenges and opportunities for our approaches to teaching, support of learning and assessment, such as streamlining personalized feedback while raising concerns about academic integrity. This article provides a research informed, expert commentary to support new pharmacology educators in navigating this complex environment. The article is neither a systematic review by design and methodology, nor is it offering comprehensive coverage of the pertinent literature (an insurmountable task, given the breadth of the topic). We highlight how educators in basic and clinical pharmacology are transforming their teaching and curricula to enhance student success in current and future settings. Global initiatives, such as those sponsored by the International Union of Basic and Clinical Pharmacology, including the Pharmacology Education Project and Core Concepts-based curricula, are offering opportunities to enhance pharmacology education by standardizing key concepts, providing open-access learning resources, and fostering international collaboration. These efforts are intended to support alignment of curricula, improve student engagement through interactive materials, facilitating a global exchange of best practices, and supporting educators in adopting innovative teaching methodologies. These initiatives require contributions from pharmacology experts across multiple countries, languages, and cultures. Consequently, this article serves as a call to action to advance innovation and inclusivity in pharmacology education. SIGNIFICANCE STATEMENT: Recent disruptions in higher education have forced educators to adapt in ways that would have previously been unthinkable. The article provides an evidence-based, expert commentary for new pharmacology educators that will assist them to thrive in this complex environment.