Journal of Pharmacology and Experimental Therapeutics最新文献

Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metabolic decline. Despite advances in identifying senescence-associated biomarkers and pathways, conventional antiaging compounds such as resveratrol and fisetin, lack regulatory approval owing to insufficient evidence from large-scale trials. Drug repurposing provides a cost-efficient strategy to target aging pathways by leveraging existing pharmacologic safety profiles. Erythropoietin (EPO) exemplifies this approach, demonstrating pleiotropic antiaging effects through modulation of cell survival pathways and tissue-protective mechanisms. Recent advancements in nonhematopoietic EPO derivatives, such as carbamylated EPO, further unlock its development potential by decoupling therapeutic benefits from erythropoietic activity. This review analyzes EPO molecular antiaging mechanisms and clinical applications in age-related diseases (2015-2025), focusing on multiorgan systemic effects and derivative development beyond anemia. SIGNIFICANCE STATEMENT: This review highlights erythropoietin (EPO) as a promising repurposed drug for combating aging, targeting hallmarks such as oxidative stress and cellular senescence. Crucially, nonhematopoietic EPO derivatives circumvent traditional safety risks while retaining multipathway protective effects in brain, cardiovascular, and metabolic tissues. By leveraging established pharmacology, EPO offers a cost-efficient strategy to advance aging interventions, addressing age-related pathologies beyond anemia.

Ocular drug delivery faces significant challenges because of the eye's complexity and anatomical barriers, such as the cornea, conjunctiva, and blood-retinal barrier, which limit drug penetration and bioavailability. Recent advances in nanotechnology-based drug delivery have led to the development of innovative delivery platforms, enabling targeted, sustained, and minimally invasive delivery for ocular diseases and injuries. This review outlines the recent advances in nanosystems-based ocular drug delivery and highlights the latest progress in targeting technologies based mainly on preclinical studies and selected clinical trial data. It covers a variety of nanosystems, including organic nanoparticles (NPs) such as liposomes, nanomicelles, nanosuspensions, nanoemulsions, dendrimers, and nanofibers. Additionally, it addresses inorganic NPs, which include gold NPs, silver NPs, silica NPs, and carbon nanotubes. Besides, we summarize the clinical challenges and regulatory aspects in nanotechnology-based ocular drug delivery. Finally, inspired by current advances and therapeutic strategies, we provide an insight into clinical applications and future research directions on nanosystems-based drug delivery. We highlight the need to overcome the challenges of using nanosystems in ocular drug delivery and fill the knowledge gap on their nanotoxicity and future development. SIGNIFICANCE STATEMENT: This review highlights recent advances in nanosystem applications for ocular drug delivery, summarizes up-to-date clinical trials utilizing nanosystems for ocular drug delivery, and discusses clinical challenges and directions for future development.

Disordered energy regulation within the kidney represents an important therapeutic target to reduce the severity of acute kidney injury and subsequent fibrosis. AMP-activated protein kinase (AMPK) is stimulated in situations of cellular energy deprivation to act as a key regulator of cellular and systemic energy metabolism. AMPK activation has been shown to be protective against renal injury and fibrosis in numerous experimental studies using metformin and aminoimidazole-4-carboxamide ribonucleotide. However, studies with these traditional AMPK activators are limited by these agents being indirect activators of AMPK, with unwanted off-target effects that may limit their use. Novel AMPK activators represent a promising new therapy in kidney protection, as well as in a range of other chronic diseases. AMPK phosphorylates multiple targets to regulate numerous pathways, thereby enabling multiple mechanisms to reduce kidney injury. This review outlines important mechanisms of renal injury and fibrosis as well as the current landscape of novel AMPK activators. It outlines experimental evidence for mechanisms of novel AMPK activators and how these relate to injury and fibrosis within the kidney. Finally, it discusses the potential of these agents, as well as current challenges in their development. SIGNIFICANCE STATEMENT: Multiple studies have identified dysregulated energy metabolism as a treatment target for kidney disease, revealing novel AMP-activated protein kinase (AMPK) activators as a promising new therapy to address this opportunity for protection against kidney injury and fibrosis. Despite this promise, novel AMPK activators are yet to find a clinical role for kidney disease or other conditions. Barriers to be considered in future studies include concerns about cardiac hypertrophy and oncogenesis as well as elucidation of precise pharmacokinetic properties. Nonetheless, the large volume of beneficial preclinical data for kidney health provides motivation for future studies to address these needs.

S100A4, a member of the S100 family of calcium-binding proteins, acts as a damage-associated molecular pattern with a central role in modulating inflammatory and fibrotic responses. Upon extracellular release, S100A4 engages receptors such as toll-like receptor 4, triggering signaling cascades that amplify proinflammatory cytokine production and promote fibrotic tissue remodeling, positioning it as a promising therapeutic target. This study describes the development and characterization of CAL101, a humanized IgG4 monoclonal antibody, which binds with high affinity to the S100A4 target-binding interface. CAL101 exhibits strong cross-species reactivity, effectively binding S100A4 from human, cynomolgus monkey, mouse, and rat. Functional assays demonstrate that CAL101 inhibits toll-like receptor 4 and transforming growth factor β pathway activation in reporter cell lines and decreases cytokine release in human monocytes and whole blood cell cultures. These findings support continued development of CAL101 as a therapeutic candidate for fibrotic and chronic inflammatory diseases. A recently completed phase I trial (ClinicalTrials.gov ID NCT05965089) established the safety, pharmacokinetic, and immunogenicity profile of CAL101. A phase II trial in patients with idiopathic pulmonary fibrosis has been initiated (ClinicalTrials.gov ID NCT06736990). SIGNIFICANT STATEMENT: This article presents the development and characterization of CAL101, a first-in-class humanized IgG4 antibody that neutralizes S100A4 by blocking its receptor interactions. CAL101 suppresses inflammatory and fibrotic signaling and is currently in phase II trial for idiopathic pulmonary fibrosis.

Severe asthma is characterized by persistent airway inflammation and structural remodeling, including mucus accumulation, epithelial thickening, and subepithelial fibrosis, which are often refractory to conventional therapies. Group 2 innate lymphoid cells (ILC2s) contribute to these pathological changes by producing large amounts of interleukin-5, interleukin-13, and amphiregulin. Although cell cycle regulators have been implicated in immune cell proliferation, their role in ILC2-driven asthma pathogenesis remains unexplored. Here, we identified the cyclin-dependent kinase (CDK) 4/6-ILC2 axis as a previously unrecognized driver of airway remodeling in severe asthma. Using an ovalbumin (OVA)-induced mouse model of severe asthma, we demonstrated that (1) CDK4⁺ and CDK6⁺ cells were elevated by 4.0- and 4.5-fold, respectively, in the lungs; (2) treatment with the CDK4/6 inhibitor palbociclib reduced fibrosis and ILC2 expansion by 77% and 87%, respectively; (3) increased ILC2s in the lungs showed high gene expression levels of CDK4, CDK6, and profibrotic factors, including fibroblast growth factor 2, fibroblast growth factor 23, collagen (COL) 4A2, COL10A1, and COL18A1; (4) thymic stromal lymphopoietin stimulation enhanced CDK4/6 protein expression in ILC2s, leading to their proliferation; and (5) palbociclib significantly inhibited the proliferation of ILC2s, at least in part by suppressing retinoblastoma phosphorylation. These findings establish CDK4/6 as a novel molecular pathway regulating ILC2-mediated airway remodeling and highlight its inhibition as a promising therapeutic approach for severe asthma. SIGNIFICANCE STATEMENT: Although cell cycle regulators have been implicated in immune cell proliferation, their role in group 2 innate lymphoid cell-driven asthma pathogenesis remains unexplored. Here, we identified the cyclin-dependent kinase 4/6-group 2 innate lymphoid cell axis as a previously unrecognized driver of airway remodeling in severe asthma.

The complex molecular pathways behind liver fibrosis (LF) make the existing antifibrotic therapy unsatisfactory. In this work, entacapone's hepatoprotective activity was examined, along with its impact on the hepatic expression of fat mass and obesity-associated protein (FTO), N6-methyladenosine (m6A), and silent information regulator (SIRT)1 in a rat model of LF. LF was induced by carbon tetrachloride (CCl₄) in a dose of 2 mL/kg orally twice weekly throughout the study. Three groups of 30 male Wistar rats were created as follows: (1) control group, (2) LF group, and (3) entacapone-pretreated group. Liver/body weight index and liver function tests were measured. Malondialdehyde, superoxide dismutase, and m6A values, as well as FTO and SIRT1 gene expression, were detected in the liver. Liver histopathology and transforming growth factor β immunohistochemical analysis were assessed. Compared with the LF group, the entacapone-pretreated group showed a decrease in oxidative stress in hepatic tissues and improved hepatic function tests. In comparison with the LF group, this was linked to a decrease in FTO gene expression and an increase in SIRT1 gene expression and the percentage of m6A in total RNA. Additionally, the entacapone-pretreated group decreased the amount of collagen fibers and transforming growth factor β expression, improving the histopathological alterations in the liver. In a rat model of LF, entacapone's hepatoprotective effect may be attributed to the alteration of the FTO/m6A/SIRT1 signaling pathway. The current study may offer entacapone as a promising approach for liver protection during fibrosis. SIGNIFICANCE STATEMENT: The current study suggests that entacapone could increase silent information regulator 1 expression through its effect on fat mass and obesity-associated protein and N6-methyladenosine modulation, providing a promising approach for protecting the liver during fibrosis and identifying a potential new molecular target for the prevention of liver fibrosis.

Parkinson's disease is the most prevalent disorder among a group of conditions known as synucleinopathies. It is characterized by the presence of intracellular inclusions composed of misfolded α-synuclein (α-Syn) protein within neurons of the central and peripheral nervous systems. The antibody-based immunotherapeutic approach has substantial promise in treating various types of synucleinopathies, including Parkinson's disease. This review critically examines the pathomechanistic impact of α-Syn on the cellular environment, with a focus on neuroinflammation and immune responses. Various strategies, including active and passive immunization, have been investigated to counteract synucleinopathies. We provide an overview of antibody-based strategies investigated in human clinical trials for the treatment of Parkinson's disease, focusing on cutting-edge approaches, including vaccination therapy, engineered antibody fragments, intrabodies, and nanobodies, designed to combat neuroinflammation-induced neurodegeneration. Harnessing immunotherapy to modulate immune activation has garnered significant interest as a potential therapeutic avenue for various inflammation-linked neurodegenerative disorders. Multiple strategies, including active and passive immunization, have been investigated to target α-Syn. The intricate process of selecting the most effective anti-α-Syn antibody for treating human synucleinopathies requires careful consideration. Additionally, the need for future research and clinical trials must prioritize unlocking the full potential of the immune system to advance our understanding of synucleinopathies. SIGNIFICANCE STATEMENT: This minireview explores recent advances in α-Syn-targeted immunotherapy, antibody fragments, intrabodies, and nanobodies. It highlights their mechanisms and potential to reshape Parkinson's disease treatment through the development of next-generation immunotherapeutics.

The relationship between neuroinflammatory processes and stress-related disorders is complex with neuroinflammation both resulting from, and contributing to, the stress response. Findings from both preclinical studies and clinical trials suggest that ibudilast (IBUD), a glial cell activation attenuator and phosphodiesterase inhibitor, has shown promise for mitigating the adverse behavioral effects of stress exposure and stress-related neuropsychiatric disorders. The objective of the present study was to determine the effect of IBUD administration on anxiety-like behavioral performance and fear memory expression in rats following stressor exposure. Here, adult male Sprague-Dawley rats were behaviorally tested in the elevated plus maze (EPM) and acoustic startle response tests 2 days before (day 1) and 2 days after (day 5) exposure to a stressor (inescapable footshock). Five days after stressor exposure, IBUD (0-10 mg/kg, i.p.) was administered 1 hour prior to a daily fear expression test session (days 8-11). Behavioral performance in the EPM and acoustic startle test was measured again on the following day (day 12). Following this, multiplex immunoassays were used to determine neuroinflammatory cytokine/chemokine levels in various brain regions. In a separate experiment, the effects of IBUD on locomotor activity and anxiety-like behavior were characterized in an open field test in rats with no history of stressor exposure. Stress exposure significantly (P < .05) reduced open arm exploration in the EPM-effects that were prolonged following IBUD treatment in a dose-dependent manner. Pretest administration of IBUD resulted in significantly (P < .05) greater freezing behavior during the fear expression tests with no evidence of fear extinction, whereas fear extinction was evident in vehicle-treated control rats. In nonstressed rats, IBUD reduced total locomotor activity and center exploration in the open field in a dose-dependent manner. Neuroinflammatory marker levels in the prefrontal cortex and amygdala were positively correlated with anxiety-like behavioral performance outcomes. Together, results suggest IBUD perpetuates stress-induced anxiety-like behavior and stress-associated fear memory expression (ie, hinders fear memory extinction). Further investigations into the interactions between IBUD administration and stressor exposure are needed to understand the implications of administering this drug in the context of stress exposure. SIGNIFICANCE STATEMENT: Ibudilast, a glial cell inhibitor and promising treatment candidate for various psychiatric disorders, was found to prolong fear expression and anxiety-like behavior in stress-exposed rats. Results suggest added characterization and consideration of its interactions with traumatic stress is needed.

The use of kratom as an alternative to conventional opioids has surged, driven largely by anecdotal reports of its efficacy for pain relief and opioid withdrawal management. The growing prevalence of kratom products enriched with 7-hydroxymitragynine (7-HMG), an active metabolite of mitragynine (MG), necessitates evaluating the respiratory effects of these alkaloids and determining whether naloxone reverses their potential respiratory depressant effects. Respiratory parameters were measured in awake, freely moving female and male Sprague-Dawley rats using whole body plethysmography. To minimize handling-induced artifacts and ensure precise respiratory recordings, drugs were administered intravenously. Morphine and 7-HMG induced significant respiratory depression, evidenced by reductions in breathing frequency, tidal volume, and minute volume. The potency of 7-HMG to decrease minute volume by 50% was 4.5-fold greater than that of morphine. In contrast, MG administration unexpectedly increased respiratory frequency. Naloxone fully reversed the respiratory depression induced by both morphine and 7-HMG but did not alter the respiratory stimulant effects produced by MG. These findings demonstrate that 7-HMG exhibits significant respiratory depressant properties similar to classical opioids, and importantly, such depressant effects are effectively antagonized by naloxone. Conversely, MG exerts respiratory stimulant effects through mechanisms independent of opioid receptor pathways. Collectively, these data highlight crucial pharmacological distinctions between kratom alkaloids, underscoring the risk associated with high 7-HMG-containing kratom products and suggesting that the predominant alkaloid MG may offer a safer respiratory profile. SIGNIFICANCE STATEMENT: The prevalence of kratom products containing 7-hydroxymitragynine (7-HMG), a μ-opioid receptor agonist, underscores the need to evaluate respiratory effects of kratom-related alkaloids and their reversal by naloxone. 7-HMG induced significant respiratory depression comparable with morphine, which was reversed by naloxone. Conversely, mitragynine, kratom's most abundant alkaloid, unexpectedly increased respiratory frequency unaffected by naloxone. These findings highlight critical pharmacological differences between kratom-related alkaloids, emphasizing potential risks associated with products containing high concentrations of 7-HMG.