The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
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200 papers
Striatal spinophilin enhances dopamine D2 receptor (D2R) interaction with cytosolic proteins to mediate persistent D2R agonist-induced locomotor suppression.
Hens B, Smith-Kinneman WR, Doud EH … +1 more , Baucum AJ
J Pharmacol Exp Ther · 2026 Jan · PMID 41506089 · Full text
Loss of dopamine neurons in Parkinson disease (PD) leads to motor deficits. Dopamine D2 receptor (D2R) agonists treat PD-associated motor deficits by acting on postsynaptic receptors located within the striatum that have...
Loss of dopamine neurons in Parkinson disease (PD) leads to motor deficits. Dopamine D2 receptor (D2R) agonists treat PD-associated motor deficits by acting on postsynaptic receptors located within the striatum that have been upregulated due dopamine loss. However, mechanisms that contribute to increased D2R activity in PD to enhance D2R function are poorly described. Spinophilin is a protein phosphatase 1 targeting protein that is expressed in postsynaptic dendritic spines and interacts with postsynaptic D2Rs. However, how spinophilin regulates D2R function is unknown. In the current study, we found that loss of spinophilin, specifically in indirect pathway medium spiny neurons and cholinergic interneurons limited the suppression of locomotion caused by the D2R agonist, quinpirole. Mechanistically, using proximity labeling in neuro2A cells and coimmunoprecipitaitons in striatal lysates from wildtype and spinophilin knockout mice, we found that spinophilin promotes the interaction of the D2R with intracellular proteins, suggesting spinophilin mediates agonist-induced D2R internalization. Therefore, our data support future studies targeting the spinophilin/D2R interaction to enhance D2R agonist activity, which may promote the efficacy of current PD therapeutics. SIGNIFICANCE STATEMENT: This manuscript demonstrates that spinophilin mediates agonist-induced D2R protein interactions with intracellular proteins and locomotor suppression. The study delineates spinophilin as a potential target to enhance the efficacy of D2R agonists, a mainstay treatment for Parkinson disease.
Emerging therapies targeting lipoprotein(a): Pharmacologic advances and future directions.
Perez AD, Simpson RJ, Komé AM … +1 more , Lopez ST
J Pharmacol Exp Ther · 2025 Dec · PMID 41478673 · Publisher ↗
Despite advances in therapies that target low-density lipoprotein (LDL), atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity and mortality. This has led to the investigation of other biomark...
Despite advances in therapies that target low-density lipoprotein (LDL), atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity and mortality. This has led to the investigation of other biomarkers, including lipoprotein(a) [Lp(a)]. Lp(a) is a variant of LDL that is genetically determined, has proatherogenic, proinflammatory, and prothrombotic effects, and has a linear correlation with ASCVD risk. Approximately 20%-30% of the global population has elevated serum Lp(a). Recommendations for increased Lp(a) testing has heightened the need for effective medications to target this biomarker. Although traditional antilipemic agents have demonstrated negligible effects on Lp(a), multiple targeted therapies are emerging, including antisense oligonucleotides, small interfering RNA agents, and small molecules. The efficacy of these novel agents observed in early clinical trials and the development of alternate treatment modalities, including gene editing and RNA-based innovations, signal a promising new era of ASCVD prevention via non-LDL pathways. SIGNIFICANCE STATEMENT: Lipoprotein(a) is a genetically determined biomarker that significantly impacts atherosclerotic risk. The development of novel therapies that lower lipoprotein(a) warrants a broad understanding to increase comfortability and optimize utilization upon market approval.
Cell penetrating peptide-functionalized small interfering RNA nanoparticles knock down HER expression in breast cancer cells.
Dissanayake R, Mishra VK, Ahmed M
J Pharmacol Exp Ther · 2025 Dec · PMID 41478672 · Full text
Efficient delivery of small interfering RNA (siRNA) remains a major challenge in gene therapy, particularly due to poor cellular uptake, enzymatic degradation, and endosomal entrapment of the cargo. Cell penetrating pept...
Efficient delivery of small interfering RNA (siRNA) remains a major challenge in gene therapy, particularly due to poor cellular uptake, enzymatic degradation, and endosomal entrapment of the cargo. Cell penetrating peptides (CPPs) offer a promising strategy for intracellular delivery of nucleic acids; however, peptide-based gene delivery carriers possess limited nucleic acid condensation capability, demonstrating reduced transfection efficacies in mammalian cells. This study aimed to enhance siRNA delivery efficacies of CPP-based siRNA therapeutics by combining nucleic acid condensation efficacies of methylated protamine with the cell permeation capabilities of cyclic peptides to improve physiological stability, cellular uptake, and gene silencing efficacies in HER2 breast cancer cells. Cyclic CPPs (cCPPs) of different cationic and amphipathic characters (namely, cTAT, cKALA, and cC105Y) were synthesized by solid phase peptide synthesis. Methylated protamine/siRNA complexes of net neutral nanoparticles (NNPs) obtained at nitrogen-to-phosphate ratio of 1 were functionalized with cCPPs at various cCPP/siRNA w/w ratios, and the sizes and net charges of the formulated nanoparticles were analyzed using dynamic light scattering and a zeta potential instrument, respectively. cCPP-functionalized NNPs demonstrated improved nucleic acid condensation efficacy and protection against enzymatic degradation compared with bare NNPs. cCPP-NNPs formulated using various types of peptides overall demonstrated superior siRNA transfection efficacies with ∼60% HER2 gene silencing efficacies in HER2 breast cancer cells. cC105Y-NNPs particularly showed improved physiological stability and cellular uptake compared with the other cCPP-functionalized nanoparticles. Endosomal escape remained a limiting factor in the gene expression efficacies of cCPP-NNPs, and incorporation of an endosome-disrupting agent improved HER2 gene knockdown efficacies (∼80%) to levels that were comparable to the Lipofectamine control. Furthermore, the potential of cCPP-NNPs for simultaneous knockdown of HER2 and HER3 was demonstrated to improve the anticancer efficacies of the nanoparticle for HER2 breast cancer treatment. SIGNIFICANCE STATEMENT: Cyclic cell penetrating peptide-functionalized nanoparticles with improved physiological stability and optimized nucleic acid condensation and release efficacies formulated by simple deposition of cationic peptides on protamine small interfering RNA complexes demonstrate superior gene knockdown and anticancer efficacies in breast cancer cells.
Nonviral DNA delivery's recent successes and final hurdles.
Tiwari S, Patel MN, Brenner JS
J Pharmacol Exp Ther · 2025 Dec · PMID 41478671 · Full text
Nonviral DNA delivery has emerged as a promising alternative to viral vectors for gene therapy because of its reduced immunogenicity, scalable manufacturing, and capability of loading larger cargos. Despite these advanta...
Nonviral DNA delivery has emerged as a promising alternative to viral vectors for gene therapy because of its reduced immunogenicity, scalable manufacturing, and capability of loading larger cargos. Despite these advantages, multiple hurdles must be addressed. The endosomal barrier poses a significant obstacle because DNA is often degraded in acidic vesicles following endocytosis. After endosomal release, DNA is sensed by the cyclic GMP-AMP synthase, a cytosolic immune sensor, leading to inflammation and lower gene expression levels. Furthermore, DNA requires nuclear entry for gene expression, which has been one of the most complex challenges for the field to progress. Recent advances have explored innovative strategies to overcome these hurdles for nonviral DNA delivery. This review highlights the current landscape of nonviral DNA delivery, focusing on intracellular barriers and recent technological breakthroughs. We further discuss future directions to overcome these challenges to develop safe, effective, and clinically translatable nonviral DNA delivery systems for a range of therapeutic applications. SIGNIFICANCE STATEMENT: Nonviral DNA delivery offers a safer, scalable alternative to viral vectors but faces key challenges such as endosomal escape, poor tolerability, and low levels of transgene expression. This review highlights the critical barriers and emerging solutions, outlining how recent advances can enable low-cost, redosable genetic medicine and DNA vaccines suited for clinical translation.
Using nanobodies for breast cancer treatment.
Galappaththi SPL, Swingle MR
J Pharmacol Exp Ther · 2025 Dec · PMID 41478670 · Publisher ↗
Despite recent advancements in breast cancer management, it remains the most common malignancy among women worldwide and is the second leading cause of cancer-related deaths in women. Therefore, there is considerable roo...
Despite recent advancements in breast cancer management, it remains the most common malignancy among women worldwide and is the second leading cause of cancer-related deaths in women. Therefore, there is considerable room for improvement in diagnostics, therapeutics, and research related to breast cancer. Although chemotherapy, radiation therapy, surgery, and targeted therapies for estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-positive breast cancers remain the standard treatments, numerous new therapeutic targets and treatment modalities are emerging. Since their discovery, nanobodies have attracted significant attention in biomedical science as research tools, diagnostic agents, and therapeutic molecules. While many studies have explored nanobodies, this mini review focuses on recent advancements in their application to breast cancer therapy. Specifically, we examine nanobody-based strategies for targeting uniquely expressed molecules in breast cancer, modulating immune responses, and facilitating nanobody-drug delivery systems, as well as how nanobodies can help overcome the limitations of current treatments. We also discuss the challenges hindering their rapid traslation into clinical practice. SIGNIFICANCE STATEMENT: Breast cancer remains a leading cause of cancer-related deaths in women. Despite substantial therapeutic progress in recent decades, it continues to pose a major global health challenge. Therefore, translating novel therapeutic modalities from the laboratory to clinical settings is critically needed.
PhRMA Foundation Trainee Challenge Award: Pharmacology of Next Generation Therapeutics.
Lee F, Miller AM
J Pharmacol Exp Ther · 2025 Dec · PMID 41478669 · Publisher ↗
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Kidney-specific delivery of a matrix metalloproteinase-2 inhibitory peptide fused to elastin-like polypeptide reduces proteinuria and renal fibrosis in a model of salt-sensitive hypertension.
Akinleye AA, Chapman HM, Roman RJ … +1 more , Bidwell GL
J Pharmacol Exp Ther · 2025 Dec · PMID 41478668 · Full text
Renal fibrosis is the hallmark and final common pathway of chronic kidney disease. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that cleave bioactive molecules to maintain extracellular matrix homeostasis....
Renal fibrosis is the hallmark and final common pathway of chronic kidney disease. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that cleave bioactive molecules to maintain extracellular matrix homeostasis. MMP-2 is upregulated in the progression of fibrosis in several models. We hypothesized that a renal-targeted MMP-2 inhibitor can slow the progression of renal fibrosis in a model of hypertension-induced renal injury. An MMP-2 inhibitory protein therapeutic was developed by fusing a known peptide inhibitor of MMP-2 (MMP-2i) to the elastin-like polypeptide (ELP) drug delivery system. Three sizes of the ELP carrier were tested to optimize the fusion protein's in vitro and in vivo performance. Activity and specificity of ELP-MMP-2i constructs for inhibition of MMP-2 were determined using in vitro MMP assays. Plasma clearance, organ biodistribution, renal accumulation, and intrarenal distribution of the fusion proteins were measured after intravenous and subcutaneous administration. The efficacy of the lead ELP-MMP-2i protein was determined using the Dahl salt-sensitive rat model of renal injury. A potent and selective inhibition of MMP-2 by ELP-MMP-2i was observed, and the construct containing the smallest ELP domain was the most potent. All fusion proteins targeted the kidneys, with the smallest fusion protein having the highest bioavailability after subcutaneous delivery. Efficacy studies with the optimized ELP-MMP-2i protein revealed that ELP-MMP-2i treatment reduced proteinuria, albuminuria, and renal fibrosis compared with vehicle-treated hypertensive rats. Renally targeted delivery of an MMP-2 inhibitor using the novel ELP drug delivery system has the potential to prevent hypertension-induced renal fibrosis and could represent a future therapy for chronic kidney disease. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first study to demonstrate the ability of a kidney-targeted selective matrix metalloproteinase-2 inhibitory peptide biologic to reduce renal fibrosis in a renal injury model.
Inhibition of equilibrative nucleoside transporters 1 and 2 by proteolysis-targeting chimeras (PROTACs).
Vignaux PA, Martinez Guerrero LJ, Raman R … +6 more , Lane TR, Perez J, Farrera DO, Wright SH, Cherrington NJ, Ekins S
J Pharmacol Exp Ther · 2025 Dec · PMID 41478667 · Publisher ↗
Proteolysis-targeting chimeras (PROTACs) are gathering considerable interest due to their ability to address previously undruggable targets. We were keen to understand the potential for these very large molecules to inte...
Proteolysis-targeting chimeras (PROTACs) are gathering considerable interest due to their ability to address previously undruggable targets. We were keen to understand the potential for these very large molecules to interact with transporters that may influence absorption, distribution, metabolism, and excretion or toxicity properties and to what extent this may be predictable using machine learning models. Consequently, we tested a set of PROTACs against several human drug transporters, namely the equilibrative nucleoside (ENT) family transporters ENT1 and ENT2, which have been directly implicated in the uptake of anticancer or antiviral drugs into target cells. We describe the dramatic inhibition observed for ENT1 and ENT2 but not for the unrelated transporter organic anion transporter 4. In addition, we report dose-response relationships for ENT1 to show some PROTACs are nanomolar inhibitors. We also explored the chemistry space of small molecules tested against ENT1 and ENT2 and compared them with PROTACs to illustrate that they are found on the periphery and close to other larger small molecules. While PROTACs are thought of as a dissimilar class to small molecules, it may be possible to bring them closer to those Food and Drug Administration-approved orally available large molecules, and in turn, increase their oral bioavailability. The outcomes of these combined in vitro and computational assessments could influence PROTAC development, be useful for their repurposing as ENT1 inhibitors for several disease indications beyond their primary one, and be used for transporter machine learning model generation and evaluation. SIGNIFICANCE STATEMENT: Proteolysis-targeting chimeras are an increasingly popular class of molecules for which we do not have a complete picture of their absorption, distribution, metabolism, and excretion or toxicity properties. For example, their interactions with uptake and efflux transporters are unknown. Here, we provide evidence that many proteolysis-targeting chimeras act as inhibitors of equilibrative nucleoside transporters 1 and 2. We hope to stimulate further study of their potential for inhibition of other transporters.
Emerging pharmacology of targeted protein degraders.
Barghout SH, Eldeeb MA
J Pharmacol Exp Ther · 2025 Dec · PMID 41478666 · Publisher ↗
Targeted protein degradation is an emerging strategy for experimental and therapeutic ablation of biologically important proteins. To elicit the degradation of their cellular targets, targeted protein degraders act by co...
Targeted protein degradation is an emerging strategy for experimental and therapeutic ablation of biologically important proteins. To elicit the degradation of their cellular targets, targeted protein degraders act by co-opting the endogenous cellular degradation machineries through chemically-induced proximity. While targeted protein degradation was serendipitously discovered as the mode of action of approved anticancer drugs including fulvestrant and thalidomide, recent years have witnessed systematic endeavors for the rational design of targeted protein degraders for diverse biological targets. Such endeavors have led to 3 major classes of targeted protein degraders including molecular glue degraders, proteolysis targeting chimeras, and hydrophobic tag-based degraders. Of these, several agents are clinically approved or currently evaluated in clinical trials for use in diseases such as cancer, neurodegenerative disorders, autoimmune and dermatologic conditions. The novel chemical and pharmacologic nature of targeted protein degraders heralds an emerging paradigm of pharmacology, known as event-driven pharmacology, which is different in many aspects from the occupancy-based pharmacology of conventional small-molecule inhibitors. In this review, we discuss the emerging pharmacology of different classes of targeted protein degraders including the molecular basis of their drug action and key pharmacologic properties pertinent to efficacy, selectivity, safety, and dosing considerations. SIGNIFICANCE STATEMENT: Targeted protein degradation is a novel strategy that establishes induced-proximity pharmacology as a promising next-generation therapeutic modality. This review provides insights into the common organizing principles of this emerging approach and the prospects for this rapidly evolving field.
Recent advances and future challenges in nanosystems for ocular drug delivery.
Shahror RA, Fouda AY
J Pharmacol Exp Ther · 2025 Dec · PMID 41478665 · Full text
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. Rec...
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.
Half-life extension of therapeutics: Applications and mechanisms.
Pathivada K, Glassman PM
J Pharmacol Exp Ther · 2025 Dec · PMID 41478664 · Publisher ↗
The clinical effectiveness of peptide and protein therapeutics is often limited by their short circulating half-life, necessitating frequent injections. Therefore, half-life extension strategies have emerged as centerpie...
The clinical effectiveness of peptide and protein therapeutics is often limited by their short circulating half-life, necessitating frequent injections. Therefore, half-life extension strategies have emerged as centerpieces in biopharmaceutical development to enhance therapeutic efficacy, reduce dosing frequency, and improve patient outcomes. A variety of approaches have been being investigated and used to prolong systemic exposure of protein drugs. Increasing hydrodynamic volume and enabling neonatal Fc receptor recycling are 2 mechanisms that are being applied to extend the half-life of many therapeutic proteins. In this review, we discuss elimination mechanisms of protein therapeutics, underlying mechanisms and strategies for their half-life extension, impact of half-life extension on primary pharmacokinetic parameters, and critical factors to be considered to choose effective half-life extension strategy. Despite these advances, challenges remain in balancing half-life extension with biological activity, stability, and manufacturability. Ongoing research aims to optimize these technologies to meet the growing demand for long-acting biologics in chronic disease management. As half-life extension continues to evolve, it holds promise not only in improving therapeutic performance but also in expanding the applicability of protein drugs across a broader range of clinical indications. SIGNIFICANCE STATEMENT: The clinical utility of many protein and peptide therapeutics is limited by insufficient circulation time. Half-life extension strategies such as PEGylation, albumin fusion, and Fc fusion have demonstrated benefits clinically and permit extended dosing windows.
mRNA and gene therapy for diabetes: The next-generation treatment frontiers.
Mourya AK, Jindal N, Kumar A
J Pharmacol Exp Ther · 2025 Dec · PMID 41478663 · Publisher ↗
Diabetes mellitus is an escalating global health challenge, with current therapies primarily focused on symptom management rather than targeting the root causes of the disease. Emerging mRNA and gene therapies offer a ne...
Diabetes mellitus is an escalating global health challenge, with current therapies primarily focused on symptom management rather than targeting the root causes of the disease. Emerging mRNA and gene therapies offer a new frontier by targeting disease mechanisms at the molecular level. This review explores the mechanistic landscape, delivery systems, and therapeutic outcomes of mRNA and gene-based interventions in diabetes. mRNA therapies, notably delivered via lipid nanoparticles, have demonstrated potential in restoring insulin production, enhancing angiogenesis, and modulating immune responses. mRNA therapy for both type 1 and type 2 diabetes using mRNAs of vascular endothelial growth factor-A, fibroblast growth factor 21, and glucagon-like peptide-1 linked to the IgG4 Fc region has shown immense potential in preclinical models of diabetes. Gene therapy for long-term correction of insulin signaling and pancreatic cell reprogramming is widely administered using viral (adeno-associated virus, lentivirus) vectors; however nonviral methods such as lipid nanoparticles and chitosan-based nanoparticles are being investigated in preclinical stages. CRISPR/Cas9 based genome-editing tools are another emerging therapeutic option for diabetes that correct metabolic defects and protect β cells. Despite these advances, delivery efficiency, immunogenicity, and off-target effects remain key translational hurdles for these therapies. Ongoing clinical trials for diabetes, including vascular endothelial growth factor A mRNA therapy for diabetic wound healing and fibroblast growth factor 21 gene therapy for type 1 diabetes, highlight the promising applications of these technologies. With careful attention to safety and pharmacokinetics, mRNA and gene therapies hold transformative promise as next-generation treatments for diabetes and its complications. SIGNIFICANCE STATEMENT: This review highlights emerging mRNA and gene therapies targeting the root causes of diabetes. By focusing on molecular mechanisms, delivery systems, and clinical advances, the review outlines next-generation strategies for treating diabetes and its complications.
Next-generation T cell engagers in oncology: Pharmacologic evolution from bispecific to trispecific antibodies.
Nahle T, Shah V, Farraj SA … +1 more , Atoui A
J Pharmacol Exp Ther · 2025 Dec · PMID 41478662 · Full text
Recent advances in immuno-oncology have led to the development of innovative T cell-engaging therapies, transforming the treatment landscape for hematologic and solid malignancies. Bispecific T cell engagers (BiTEs) have...
Recent advances in immuno-oncology have led to the development of innovative T cell-engaging therapies, transforming the treatment landscape for hematologic and solid malignancies. Bispecific T cell engagers (BiTEs) have demonstrated clinical efficacy by redirecting T cell cytotoxicity toward tumor cells, yet challenges such as antigen escape, safety concerns, and limited durability remain. Building on the foundation established by BiTEs, the emergence of trispecific T cell engagers promises enhanced tumor selectivity, improved pharmacodynamic profiles, and potentially superior clinical outcomes. This minireview summarizes the pharmacology of T cell engagers, with a focus on the mechanistic evolution from BiTEs to next-generation trispecific antibodies. We highlight recent advances in molecular design, summarize current clinical evidence, and address ongoing challenges in drug development and safety. By critically synthesizing the latest preclinical and clinical findings, this review aims to inform future research directions and optimize the clinical translation of next-generation T cell-engaging therapeutics. SIGNIFICANCE STATEMENT: This minireview synthesizes current knowledge on the pharmacology of T cell engagers, spotlighting the shift from bispecifics to trispecifics, and provides insights essential for advancing safer and more effective immunotherapies in oncology.
A review of targeted drug delivery with antibody-drug complexes.
Sanjanwala D, Meng Y, Guo Z … +1 more , Bordeau B
J Pharmacol Exp Ther · 2025 Dec · PMID 41478661 · Full text
Monoclonal antibodies are a versatile platform for targeted drug delivery. Their high specificity and favorable pharmacokinetics allow for selective drug delivery to targeted cells. A primary drug delivery application is...
Monoclonal antibodies are a versatile platform for targeted drug delivery. Their high specificity and favorable pharmacokinetics allow for selective drug delivery to targeted cells. A primary drug delivery application is antibody-drug conjugates (ADCs), which combine monoclonal antibodies with cytotoxic payloads via covalent linkers. While ADCs have shown remarkable clinical success, several limitations remain, including complex conjugation chemistries, heterogeneity in drug-to-antibody ratios, exposed hydrophobic patches, and off-target payload release, which can result in systemic toxicity. To complement existing ADC platforms and mitigate some of these issues, alternative formats referred to as antibody-drug complexes (ADCx) have been developed. ADCx are generated by forming reversible, high-affinity complexes between antibodies and drugs or preformed drug conjugates. This review discusses the ADCx formats reported to date, focusing on the unique advantages and potential limitations of each format. SIGNIFICANCE STATEMENT: Antibody-drug complexes offer a modular, noncovalent alternative to traditional antibody-drug conjugates. This review comprehensively evaluates antibody-drug complex formats, highlighting their potential to expand the utility of antibody-based drug delivery for next-generation therapeutics.
Cell-free therapy using exosomes: Advancements in the field of dermatology and cosmetology.
Anusree KP, Aparna K, Priya S
J Pharmacol Exp Ther · 2025 Dec · PMID 41478660 · Publisher ↗
Exosomes are a category of extracellular vesicles with a 30-150 nm diameter that serve as carriers of distinct and functional biomolecules, such as lipids, nucleic acids, and proteins. They are released by almost all typ...
Exosomes are a category of extracellular vesicles with a 30-150 nm diameter that serve as carriers of distinct and functional biomolecules, such as lipids, nucleic acids, and proteins. They are released by almost all types of cells and mirror the characteristics of their originating cells, making them appealing for use in cell-free therapeutic applications. The skin is the largest organ of the body. It protects the entire body from the harsh environment, helps to maintain body temperature, supports life for all other body parts, plays a significant role in regulating the immune system, etc. Interventions in dermatology and cosmetology help to maintain good-looking and healthy skin. Exosomes have assumed a prominent position in cosmetics and dermatology by facilitating cellular regeneration. Recent studies have highlighted the efficacy of exosomes as effective antioxidants in therapy approaches such as hair regeneration, skin aging reversal, scar prevention, wound healing, dermatological diseases. This article explores the therapeutic applications and clinical interventions of exosomes in cosmetology and dermatology. It also discusses the challenges and prospects in the field. SIGNIFICANCE STATEMENT: Cell-free therapy using exosomes is an emerging area in disease management. Exosomes, nanosized extracellular vesicles, play a prominent role in various conditions such as hair growth and regeneration, reversal of aging, wound healing, and management of many skin-associated diseases, such as psoriasis, dermatitis, etc. This review describes the recent developments in the utilization of exosomes in dermatological and cosmetological treatment aspects, their regulatory issues, and current status of clinical trials.
Pharmacological considerations for next-generation protein therapeutics in cardiovascular disease.
Lin E, Momin N
J Pharmacol Exp Ther · 2025 Dec · PMID 41478659 · Full text
Cardiovascular disease (CVD) remains the leading cause of death worldwide despite decades of therapeutic advances. Emerging insights into its etiology have revealed previously unappreciated cellular and molecular drivers...
Cardiovascular disease (CVD) remains the leading cause of death worldwide despite decades of therapeutic advances. Emerging insights into its etiology have revealed previously unappreciated cellular and molecular drivers beyond traditional risk factors, prompting the development of treatments that target newly identified culprit proteins and cells within cardiovascular tissues. Protein-based biologics-particularly monoclonal antibodies and multispecific proteins-are known for their strength and specificity in targeting and their established use as treatments for other diseases. However, extending biologics to new indications faces challenges: achieving durable effects in diseased tissues and minimizing side effects in healthy tissue. Addressing these long-standing challenges requires fine-tuning biologics' pharmacokinetic properties and pharmacodynamic effects according to target- and disease-specific requirements. In this review, we examine foundational pharmacokinetic and pharmacodynamic principles in the context of cardiovascular-targeted biologics, highlighting the role of protein design in controlling distribution, efficacy, and safety. Additionally, we discuss emerging preclinical and clinical biologics specifically designed for CVDs, as well as emerging opportunities in this landscape. These advances point toward a future where pharmacokinetics guide the rational design of next-generation protein therapeutics for CVD. SIGNIFICANCE STATEMENT: Protein-based biologics hold promise for treating cardiovascular diseases (CVD); however, their successful translation requires understanding how proteins' properties and cardiovascular physiology shape pharmacokinetic and pharmacodynamic behavior. This minireview connects foundational pharmacology principles with strategies in protein engineering suitable for CVD applications. Pharmacokinetic-guided design will accelerate the development of protein therapies that can transform CVD treatment.
Pharmacology of next generation therapeutics.
Glassman PM, Nguyen J
J Pharmacol Exp Ther · 2025 Dec · PMID 41478658 · Publisher ↗
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Metabolic characteristics and antidepressant mechanism of cerebroprotein hydrolysate oral liquid via regulating tyrosine hydroxylase and neurotransmitter balance.
Zhou Z, Wang Z, Zhang T … +10 more , Liu Y, Chen Q, Zhang T, Liu W, Shen Y, Hu K, Ding K, Yu T, Wang G, Liang Y
J Pharmacol Exp Ther · 2026 Jan · PMID 41475181 · Publisher ↗
Depression is a major global public health challenge, with current treatments often limited by suboptimal efficacy and adverse effects. This study investigated the antidepressant potential of cerebroprotein hydrolysate o...
Depression is a major global public health challenge, with current treatments often limited by suboptimal efficacy and adverse effects. This study investigated the antidepressant potential of cerebroprotein hydrolysate oral liquid (CHOL), a neuroprotective peptide-based solution derived from porcine brain through enzymatic hydrolysis. In model mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS), CHOL was found to significantly attenuate depressive-like behaviors. Furthermore, CHOL also effectively reduced corticosterone-induced cell damage in PC12 cells. Metabolomic analysis revealed that depression modeling led to significant disturbances in neurotransmitter-related metabolites, especially norepinephrine, whereas CHOL could restore these metabolites in key brain regions and serum. Mechanism exploration revealed that the elevation of norepinephrine by CHOL was achieved through upregulation of tyrosine hydroxylase expression. Pharmacokinetic studies demonstrated that the 8 peptides in CHOL could rapidly distribute to the brain, with serine proteases, cysteine proteases, and metalloproteases identified as the key enzymes mediating CHOL metabolism. These findings underscored CHOL's preventive and therapeutic potential and provided mechanistic insights for its development as a novel antidepressant strategy. SIGNIFICANCE STATEMENT: This study integrated multiple depression models to confirm the significant antidepressant effects of cerebroprotein hydrolysate oral liquid. For the first time, we elucidated its underlying mechanism by regulating tyrosine hydroxylase expression and promoting norepinephrine synthesis. Furthermore, 8 brain-penetrant peptides were identified, and a targeted protease-inhibition strategy was developed to enhance in vivo exposure, thereby providing novel mechanistic insights and potential translational applications in depression therapeutics.
An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
Billon C, Appourchaux K, Côté I … +1 more , Burris TP
J Pharmacol Exp Ther · 2026 Jan · PMID 41421047 · Publisher ↗
Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs...
Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.
"Letter to the Editor: Pharmacological study of the safety, efficacy, and potential of M201-A on paroxysmal and persistent atrial fibrillation".
Aphale P, Dokania S, Shekhar H
J Pharmacol Exp Ther · 2026 Jan · PMID 41418593 · Publisher ↗
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