Botulinum Toxin

Abstract

DaxibotulinumtoxinA for injection (DAXI), a novel botulinum toxin (BoNT) formulated with a custom-engineered peptide, was recently approved for treating cervical dystonia (CD). DAXI demonstrated a long duration of symptom relief in Phase 3 trials.

Abstract

This study aimed to evaluate the therapeutic impact of Onabotulinumtoxin A (botulinum toxin) injections in patients suffering from chronic migraine and chronic tension-type headache, while assessing changes in salivary pain biomarkers-calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). A total of 45 subjects were recruited: 25 diagnosed with chronic migraine and 20 with chronic tension-type headache, based on criteria from the International Classification of Headache Disorders (ICHD-3 and ICHD-2 revisions, respectively). Diagnosis confirmation was supported by MRI or CT imaging to exclude other etiologies. Salivary CGRP and PACAP levels were measured before and after botulinum toxin administration using enzyme-linked immunosorbent assay (ELISA). In this open-label, uncontrolled design, results showed a statistically significant reduction (p < 0.05) in both biomarkers post-treatment across both patient groups. Onabotulinumtoxin A demonstrated apparent effectiveness as a prophylactic therapy, contributing to notable improvement in headache symptoms. Among all clinical parameters evaluated, orofacial pain showed the highest responsiveness to treatment.

Abstract

This study aims to elucidate the mechanism by which Xuebijing Injection ameliorates acute lung injury(ALI) through promoting efferocytosis and suppressing inflammatory responses based on proteomics and experimental validation. Forty male Sprague Dawley(SD) rats were randomly divided into a normal control group and a model group. An ALI rat model was established by intraperitoneal injection of lipopolysaccharide(LPS). Successfully modeled rats were then randomized into three groups: a model control group, an Xuebijing Injection(8 mL·kg~(-1)) group, and a dexamethasone(5 mg·kg~(-1)) group, with 10 rats in each group. Intraperitoneal injection was administered for three days. Lung edema was evaluated by the wet/dry weight(W/D) ratio of lung tissue. Inflammatory infiltration and injury in lung tissue were assessed by hematoxylin-eosin(HE) staining, and the level of inflammatory cytokines, including interleukin(IL)-17, IL-18, and IL-4, as well as the anti-inflammatory molecule transforming growth factor-β1(TGF-β1) in serum was measured by enzyme-linked immunosorbent assay(ELISA). Differentially expressed genes(DEGs) in lung tissue among the normal control group, the model control group, and the Xuebijing Injection group were analyzed by proteomic sequencing, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were utilized for pathway enrichment analysis. Apoptotic cells were quantified by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) assay, and the expression of efferocytosis-related key factors in lung tissue including protein S1(ProS1), Mer proto-oncogene tyrosine kinase(MerTK), and Ras-related C3 botulinum toxin substrate 1(Rac1) was evaluated by quantitative polymerase chain reaction(qPCR), Western blot, and immunofluorescence. The results of the W/D ratio of lung tissue and pathological staining showed that lung edema, inflammatory infiltration, and injury in ALI rats were ameliorated after Xuebijing Injection intervention. ELISA demonstrated that Xuebijing Injection significantly increased the TGF-β1 level and decreased the levels of IL-17, IL-18, and IL-4. Proteomics and KEGG analysis revealed that DEGs associated with anti-ALI treatment by Xuebijing Injection were enriched in signaling pathways such as efferocytosis, apoptosis, and inflammatory response. The TUNEL staining results showed that Xuebijing Injection could significantly reduce the apoptosis rate of cells in lung tissue. qPCR, Western blot, and immunofluorescence showed that Xuebijing Injection could promote the expression of key factors ProS1, MerTK, and Rac1 involved in efferocytosis. Xuebijing Injection significantly alleviates inflammatory infiltration and injury in the lung tissue of ALI rats by enhancing efferocytosis in alveolar macrophages and promoting apoptotic cell clearance to suppress inflammation.

Abstract

Botulinum toxin A (BtxA) injection for AdLD is typically performed approxiamately every 3 months. DaxibotulinumtoxinA-lanm (Daxi) is a peptide-formulated neuromodulator with reported longer therapeutic duration. This study compared the safety and efficacy of Daxi to historical BtxA results in AdLD patients.

Abstract

Botulinum toxin type A (BoNT-A) formulations are extensively employed in aesthetic and therapeutic dermatology. However, their immunomodulatory and pro-inflammatory properties remain incompletely characterized, particularly concerning dermal fibroblasts.

Abstract

This article aims to point out new perspectives opened by genomics and epigenomics in skin rejuvenation strategies which target the main hallmarks of the ageing. In this respect, this article presents a concise overview on: the clinical relevance of the most important clocks and biomarkers used in skin anti-ageing strategy evaluation, the fundamentals, the main illustrating examples preclinically and clinically tested, the critical insights on knowledge gaps and future research perspectives concerning the most relevant skin anti-ageing and rejuvenation strategies based on novel epigenomic and genomic acquisitions. Thus the review dedicates distinct sections to: senolytics and senomorphics targeting senescent skin cells and their senescent-associated phenotype; strategies targeting genomic instability and telomere attrition by stimulation of the deoxyribonucleic acid (DNA) repair enzymes and proteins essential for telomeres' recovery and stability; regenerative medicine based on mesenchymal stem cells or cell-free products in order to restore skin-resided stem cells; genetically and chemically induced skin epigenetic partial reprogramming by using transcription factors or epigenetic small molecule agents, respectively; small molecule modulators of DNA methylases, histone deacetylases, telomerases, DNA repair enzymes or of sirtuins; modulators of micro ribonucleic acid (miRNA) and long-non-coding ribonucleic acid (HOTAIR's modulators) assisted or not by CRISPR-gene editing technology (CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats); modulators of the most relevant altered nutrient-sensing pathways in skin ageing; as well as antioxidants and nanozymes to address mitochondrial dysfunctions and oxidative stress. In addition, some approaches targeting skin inflammageing, altered skin proteostasis, (macro)autophagy and intercellular connections, or skin microbiome, are very briefly discussed. The review also offers a comparative analysis among the newer genomic/epigenomic-based skin anti-ageing strategies vs. classical skin rejuvenation treatments from various perspectives: efficacy, safety, mechanism of action, evidence level in preclinical and clinical data and regulatory status, price range, current limitations. In these regards, a concise overview on senolytic/senomorphic agents, topical nutrigenomic pathways' modulators and DNA repair enzymes, epigenetic small molecules agents, microRNAs and HOTAIRS's modulators, is illustrated in comparison to classical approaches such as tretinoin and peptide-based cosmeceuticals, topical serum with growth factors, intense pulsed light, laser and microneedling combinations, chemical peels, botulinum toxin injections, dermal fillers. Finally, the review emphasizes the future research directions in order to accelerate the clinical translation of the (epi)genomic-advanced knowledge towards personalization of the skin anti-ageing strategies by integration of individual genomic and epigenomic profiles to customize/tailor skin rejuvenation therapies.

Abstract

Background: Abdominal wall hernias represent a significant global surgical burden, with over 20 million repairs performed annually. The convergence of rising obesity and diabetes rates with complex hernia management has necessitated innovative preoperative optimization strategies that address both metabolic dysfunction and mechanical challenges. Objectives: This comprehensive review synthesizes current evidence on emerging pharmacologic and procedural optimization strategies for patients undergoing abdominal wall hernia repair, with particular emphasis on glucagon-like peptide-1 (GLP-1) receptor agonists, botulinum toxin A (BTA) injections, progressive preoperative pneumoperitoneum (PPP) and biomechanical calculated repair. Methods: We conducted an extensive literature review incorporating recent clinical trials, observational studies, and meta-analyses, focusing on metabolic optimization with GLP-1 receptor agonists, mechanical preparation techniques, and their comparative effectiveness in reducing perioperative complications and hernia recurrence. Results: GLP-1 and GLP-1/GIP agonists demonstrate substantial metabolic benefits including weight reduction (10-20%), improved glycemic control, reduced systemic inflammation, and decreased postoperative complications in surgical populations. Recent evidence suggests reduced surgical site infection, thromboembolic events, and wound dehiscence in GLP-1 receptor agonists users. However, concerns regarding delayed gastric emptying and aspiration risk require careful perioperative management. BTA and PPP remain valuable techniques for mechanical optimization in loss-of-domain hernias, though modern biomechanically calculated repair (BCR) approaches using cyclic load analysis may reduce their necessity in many cases. The GRIP/CRIP concept demonstrates superior outcomes with 5-7% five-year recurrence rates compared to 15% with conventional approaches. Emerging evidence highlights collagen metabolism dysfunction as a fundamental determinant of hernia recurrence, prompting development of collagen-focused prehabilitation programs incorporating nutritional supplementation, aquatic exercise, and targeted physical conditioning. Conclusions: A paradigm shift toward integrated, personalized preoperative optimization is emerging, combining metabolic conditioning with mechanical preparation based on individual patient phenotypes and hernia complexity. Future research should focus on comparative effectiveness trials, optimal timing protocols, and multimodal strategies to maximize surgical outcomes while minimizing complications.

Abstract

Understanding the negative regulatory mechanisms of immune cell functions is essential for developing effective tumor immunotherapy strategies. Macrophages play a crucial role in antitumor immunity; however, the mechanisms that negatively regulate their antitumor functions remain incompletely understood. TIPE2 is known to be a critical regulator of various immune cells, but its role as a negative regulator of macrophage antitumor functions has not yet been established.

Abstract

Migraine, particularly in its chronic and treatment-resistant forms, imposes a significant burden on patients. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway (anti-CGRP mAbs) and onabotulinum toxin type A (BTX-A) have emerged as key preventive treatments for resistant migraine. However, direct comparisons between these therapies remain limited.

Abstract

BackgroundChronic migraine (CM) is highly disabling, and many patients fail to respond to monotherapy with approved preventive treatments. OnabotulinumtoxinA (BoNTA) and atogepant act on distinct but complementary targets within the trigeminovascular system and may exert additive or synergistic effects when used together. Real-world data on their combination remain scarce.MethodsWe prospectively analyzed adult patients with CM who had received at least three prior BoNTA cycles and initiated atogepant 60 mg/day for a minimum of 24 weeks as add on to BoNTA. Co-primary outcomes were changes in monthly migraine days (MMDs) and ≥50% response rate at 24 weeks. Secondary outcomes included disability, medication use, tolerability and subgroup comparisons by prior monoclonal antibodies exposure.ResultsAmong 101 patients, 82 completed 24 weeks of co-treatment. Mean MMDs decreased by 6.5 days (p < 0.001) and 45.1% of patients achieved a ≥50% reduction. Acute medication days decreased by 6.0 (p < 0.001) and Headache Impact Test-6 scores improved significantly (mean change: -4.0; p < 0.001). Patient's Global Impression of Change scores indicated moderate-to-great improvement. Anti-calcitonin gene-related peptide naïve patients experienced larger reductions in MMDs (-7.75 vs. -5.87) and disability scores compared to non-naïve patients. Multivariable analysis identified only baseline acute medication use as predictor of response. Adverse events were mild and consistent with known safety profiles for both drugs separately; no novel safety concerns emerged.ConclusionsThe addition of atogepant to BoNTA might be effective and well tolerated in real-world setting, including CM patients previously exposed to multiple preventives. Prospective controlled trials and health-economic evaluations are warranted to validate these observations and inform future clinical guidelines.

Abstract

There is currently limited knowledge about the combined effect of Botulinum toxin type A (BoNT/A) and Platelet-rich plasma (PRP) on hair follicle growth and reconstruction. This study aimed to investigate the impact of BoNT/A in conjunction with PRP on hair follicles and explore its underlying mechanisms. The levels of alkaline phosphatase (ALP), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and versican levels were assessed to determine their influence on hair follicle growth. Hair follicle quantification was performed, while β-catenin and Ki-67 expression levels were analyzed. The concentrations of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured as inflammatory biomarkers. Western blot analysis measured stathmin 1 (STMN1) expression and quantified key Wnt/β-catenin signaling pathway components. The findings demonstrated that the conjunction of BoNT/A and PRP effectively enhanced hair follicle growth. It promoted the upregulation of ALP, FGF, PDGF, VEGF, and versican, increased hair follicle number, upregulated ALP levels, and enhanced the expression of β-catenin and Ki-67. It also markedly decreased the concentrations of IL-6 and TNF-α, potentially inhibiting hair follicle miniaturization by mitigating inflammation. The combined treatment promotes hair follicle growth by activating the Wnt/β-catenin pathway through STMN1 upregulation. BoNT/A in conjunction with PRP facilitates hair follicle growth and reconstruction through STMN1 protein modulation and Wnt/β-catenin pathway activation.

Abstract

Botulinum neurotoxin type A formulations all contain the same 150 kDa core protein, yet they behave as if they were different drugs. Clinicians routinely observe differences in onset, spread, duration, and immunogenicity, despite the fact that accessory proteins dissociate quickly after injection. If dissociation were the full story, these products should act identically. They do not. Using a multiscale in silico AesthetiSIM™ platform and a 10,000-patient digital twin cohort. Simulations were performed under physiologic temperature (37 °C) and pH 7.4, with sensitivity analyses evaluating these conditions. Our simulations confirmed that dissociation alone cannot account for divergent clinical profiles. Instead, excipients and microenvironmental factors create distinct pharmacokinetic and immunologic landscapes that persist even when the neurotoxin core is identical. Lactose drove broader diffusion, sucrose stabilized local confinement, sodium chloride altered electrostatic spread, and the peptide RTP004 prolonged residence by binding extracellular proteoglycans. These formulation-specific interactions shaped receptor engagement, clearance, and immunogenicity, overturning the assumption that dissociation explains everything. The findings demand a shift in perspective: botulinum toxins are not defined solely by their neurotoxin, but by the excipient ecosystem in which they are delivered. This mechanistic framework explains why products remain "non-interchangeable" and shows that the paradox of dissociation is not a paradox at all; it is the predictable outcome of pharmacology embedded in formulation. As these outcomes are derived from computational modelling, they should be viewed as predictive and require confirmation through targeted biochemical, biophysical, and cell-based assays.

Abstract

Semaglutide, a GLP-1 (glucagon-like peptide-1) receptor agonist, is widely prescribed for weight loss in non-diabetic populations. Given the link between obesity and overactive bladder (OAB), we explored whether GLP-1 use would improve adverse urinary events beyond its weight loss benefit for non-diabetic adults undergoing onabotulinumtoxin A (BTX-A) treatment for OAB. Using the TriNetX database, we conducted a retrospective cohort study of non-diabetic OAB patients treated with BTX-A alone or with concurrent GLP-1 therapy. Propensity score matching (1:1) was adjusted for age, race, ethnicity, hypertension, and BMI/obesity. After matching, 992 patients were included in each group. GLP-1 use was associated with a lower incidence of urinary retention (8.6% vs. 4.9%, risk difference 3.66%, p = 0.0044) and urinary tract infection (13.3% vs. 8.8%, risk difference 4.54%, p = 0.00224), with corresponding improved one-year retention-free and UTI-free survival on Kaplan-Meier (KM) analysis. Antispasmodic initiation rates were similar (11.8% vs. 10.3%, risk difference 1.55%, p = 0.6921), and KM analysis showed no significant difference. These findings suggest that GLP-1 receptor agonist use may improve select urinary adverse events in non-diabetic adults undergoing BTX-A treatment for OAB and support further investigation into its potential adjunctive role in OAB management with longer follow-up.

Abstract

The bladder trigone is an anatomically and functionally distinct region within the lower urinary tract (LUT), characterized by a dense network of afferent sensory fibers, specialized urothelial interactions, and prominent mechanotransduction mechanisms. Its intricate neuroarchitecture enables precise detection of bladder filling and coordination of micturition, whereas dysregulation of these pathways contributes to lower urinary tract symptoms (LUTS), including urgency, frequency, and bladder pain. Despite its recognized clinical relevance, the structural and functional basis of trigonal sensory signaling - and its role - remain incompletely understood. This review synthesizes current evidence on trigonal afferent organization, integrating data from anatomical mapping, receptor profiling, electrophysiological characterization, and translational research. Seminal anatomical observations are combined with recent advances in mechanotransduction and purinergic, peptidergic, and transient receptor potential (TRP) signaling to provide a comprehensive perspective. The trigone exhibits three principal afferent classes: (1) intraepithelial fibers penetrating umbrella cells, marked by P2X purinoceptor 3 (P2X3), transient receptor potential vanilloid 1 (TRPV1), calcitonin gene-related peptide (CGRP), and substance P (SP); (2) subepithelial plexuses surrounding microvasculature, enriched in vasoactive neuropeptides and exhibiting plastic hypertrophy in overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS); and (3) encapsulated corpuscular endings at the lamina propria-detrusor junction, expressing PIEZO1/2 and acid-sensing ion channels (ASICs) for rapid adaptation. In trigeminal dorsal root ganglion (DRG) neurons, high expression of PIEZO2, P2RX3, and voltage-gated sodium channel, type 1.8 (Nav1.8) was observed, revealing their role as the foundation for multisensory information processing. Functional assays highlight distinct mechanotransductive and chemosensory pathways, with aging, inflammation, and neurotrophic factors driving afferent plasticity underlying abnormal bladder sensation, such as urgency, frequency, and pain. Early clinical trials of P2X3 antagonists and intravesical TRPV1 inhibitors demonstrate promising symptomatic benefits. Collectively, evidence positions the bladder trigone as a critical sensory hub where neuronal, urothelial, and immune signals converge to regulate bladder sensation. Understanding its molecular and structural specialization may inform the development of region-specific neuromodulatory therapies targeting sensory urgency and afferent-driven bladder dysfunction.

Abstract

The purpose of this study is to evaluate whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with periorbital changes in patients with type 2 diabetes mellitus (T2DM) or obesity.

Abstract

The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system in mice. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.

Abstract

The mechanism linking extracellular amyloid beta (Aβ) with intraneuronal tau tangles, pathological hallmarks of Alzheimer's disease (AD), is not understood; it was tested in the current study through Aβ binding partners.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed metabolic and aesthetic medicine, yet their potential influence on botulinum toxin type A (BoNT-A) pharmacodynamics remains unexplored. Using the AesthetiSIM™ microsimulation platform, a transparent, parameterized in-silico model was developed to estimate whether GLP-1-related changes in metabolism and neuromuscular recovery could alter toxin durability. Twenty-five thousand virtual patients were generated, representing two domains of BoNT-A use: chronic migraine (n = 20,000) and masseter prominence (n = 5000). Virtual subjects were randomly assigned to semaglutide, tirzepatide, liraglutide, dulaglutide, or control conditions, and simulated over one year under standardized 100-unit BoNT-A dosing. The framework incorporated three mechanistic domains-synaptic modulation via cAMP-PKA-mediated SNAP-25 phosphorylation, lean-mass reduction affecting diffusion kinetics, and systemic metabolic variability reflecting diabetic or rapid-weight-loss phenotypes. In chronic migraine, mean BoNT-A duration declined from 14.0 ± 2.3 weeks in controls to 12.6, 12.5, 12.2, and 11.8 weeks across GLP-1 exposures (all p < 0.001; hazard ratio range 1.54-1.95). In masseter prominence, mean duration decreased from 20.1 ± 2.9 weeks to 17.3, 17.0, 16.7, and 16.2 weeks, with hazard ratios 1.72-2.08. Early wear-off and uncovered symptomatic periods rose proportionally across agents, with the hierarchy tirzepatide > liraglutide > dulaglutide > semaglutide. Sensitivity analyses indicated that approximately 55 % of the reduction in duration was attributable to synaptic modulation, 30 % to lean-mass decline, and 15 % to metabolic variability. These findings suggest a biologically plausible interaction between GLP-1 signalling and BoNT-A recovery dynamics. The results are exploratory and derive entirely from computational modelling rather than clinical observation. Experimental validation-such as neuronal culture assays or prospective patient cohorts-is required before any modification of treatment intervals or dosing practices can be considered.

Abstract

Migraine, a common primary headache disorder, ranks second only to low back pain as a leading cause of disability. Proposed mechanisms include vasodilation, trigeminovascular activation, and neurogenic inflammation. Diagnosis is clinical, as no biomarker exists, and the International Classification of Headache Disorders-3 has clinical criteria for diagnosis. Differentiating migraine from other conditions can be challenging, with "red" and "green flags" guiding assessment. Treatment includes acute and preventive options, with calcitonin gene-related peptide inhibitors and neuromodulation as newer strategies. Complementary therapies and botulinum toxin injections may also benefit those with chronic migraine.

Abstract

In this study, for the first time, nanobody conjugated beads were developed to enrich botulinum serotype A. We evaluated two types of nanobody A8-functionalized magnetic beads, both of which effectively captured and enriched BoNT/A from dilute solutions and complex protein mixtures, achieving a concentration increase of approximately 12- to 30-fold. The A8@N-beads showed higher binding capacity than the A8@S-beads, suggesting that our self-synthesized NH2 beads work well in this application. Our data serve as evidence that using different bead types with nanobody conjugation is a promising enrichment approach for further detection of Lc/A, particularly in applications involving low-abundance targets or complex sample matrices, such as food safety screening or clinical diagnostics.

Abstract

Surface adsorption of proteins in bulk drug product formulations and loss of protein structural integrity during manufacturing processes can diminish drug potency. In formulations containing low biologic drug substance, such as botulinum toxin type A (BoNTA) products, loss of active protein is a major concern. To mitigate the risk of activity loss, most commercial BoNTA products contain an abundance of human serum albumin (HSA, 125-1000 µg/vial) to prevent adsorption of BoNTA to container surfaces by competing for nonspecific binding sites. The stabilizing ability of HSA is well established; however, there are notable potential safety concerns surrounding its use as an excipient. Our data suggests that at pH 5.5, in the presence of increasing concentrations of HSA the 150 kDa BoNTA core neurotoxin (RTT150) may form aggregate complexes with HSA when heated to 45-50 °C, in a dose-dependent manner. A new BoNTA product has recently been approved with a unique formulation which uses a proprietary synthetic cationic peptide (RTP004) to replace HSA as a stabilizer. Here, we show that RTP004 binds to the core neurotoxin and enhances its thermostability. In combination with polysorbate 20 (PS20), RTP004 efficiently and completely prevents surface adsorption of the 150 kDa core neurotoxin and stabilizes the biologic drug substance during manufacturing processes, even at concentrations 10- to 100-fold less than those used for HSA in commercial BoNTA products. Thus, the combination of RTP004 and PS20 forms the basis for a novel and effective BoNTA formulation, removing the need for HSA and thereby avoiding its theoretical safety risks and documented limitations.

Abstract

Botulinum toxin type A (BTA) is widely used in dermatologic procedures. While its anti-fibrotic effects on fibroblasts are well established, its role in keratinocyte-driven inflammation and pruritus during wound healing remains underexplored.

Abstract

anti-CGRP monoclonal antibodies (anti-CGRP mAbs) represent a highly effective prophylactic treatment for chronic migraineurs, but for some subjects they are ineffective. We aimed to determine if OnabotulinumtoxinA (BoNT/A) treatment may be helpful in these cases. We collected data from fourteen chronic migraineurs who attended our Headache Center and who did not benefit from anti-CGRP mAbs treatment. After anti-CGRP mAbs failure, these patients underwent at least one BoNT/A treatment according to the PREEMPT protocol. We then compared the variation in headache days (DOH), pain intensity (NRS), and symptomatic medication intake (ADI) before and after anti-CGRP mAbs therapy and before and after BoNT/A treatment: we confirmed that the interruption of anti-CGRP mAbs treatment had actually been due to a lack of benefit in terms of DOH (19.21 ± 7.58 days and 20.29 ± 8.32 days; p = 0.74), NRS (7.64 ± 0.75 vs 7.57 ± 1.01; p = 0.85) and ADI (42.86 ± 52.74 vs 45.64 ± 52.82; p = 0.79). All patients started BoNT/A therapy after discontinuing anti-CGRP mAbs. After a period without treatment, therapy with BoNT/A caused a significant reduction in DOH (23.86 ± 6.97 vs. 11.36 ± 10.10, p = 0.010), ADI (47.07 ± 51.19 vs. 20.50 ± 21.42, p = 0.010) and NRS (8.07 ± 1.00 vs. 6.64 ± 1.60, p = 0.014), improving clinical conditions in patients non-responders to anti-CGRP mAbs. It is not well established on which basis pharmacological resistance to anti-CGRP mAbs develops in such refractory patients. Still, these data may point towards a mechanism of pain relief that could not be solely related to CGRP pathways activity, thus being a good rescue therapy in resistant headache management, although further data are needed. Our preliminary results suggest that BoNT/A may be a promising salvage therapy option when anti-CGRP mAbs are ineffective, but evidence requires confirmation from basic research and in larger, uncontrolled, prospective studies in chronic migraineurs.

Abstract

As global populations age, the clinical approach to managing migraine must evolve. Migraine in older adults presents unique treatment challenges due to comorbidities, poor adherence to treatment, altered pharmacokinetics, and polypharmacy. Injection -based preventive treatments such as onabotulinumtoxinA (BoNT-A), greater occipital nerve blocks (GONB), and anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) offer promising alternatives. This narrative review highlights the underrepresentation of older adults in migraine clinical trials and summarizes the effectiveness and safety of BoNT-A, GONB, and CGRP mAbs in patients over 65 years of age. To identify relevant studies addressing migraine management in the older adults, we conducted a comprehensive literature search of PubMed, Embase, and Cochrane Library. The search was limited from the past ten years, up to 5 April 2025. Studies were included if clinical trial, observational, real-world data, or review examined migraine treatment in adults over 65 years, with separate data according to age. A total of 22 studies were included: 4 on BoNT-A, 2 on GONB, 13 on anti-CGRP mAbs, and 3 reviews on injectable therapies. BoNT-A has shown significant benefits in reducing migraine frequency, acute medication use, and disability in real-world settings though randomized trials did not include older adults. GONB has demonstrated high response rates in older adults, although there was no separate analysis for patients over 65 years of age in randomized controlled trials. In contrast, CGRP mAbs have increasingly included in trials, with some trials enrolling patients up to 75 years. Subgroup analyses and real-world data support their comparable effectiveness and safety in older adults. BoNT-A, GONB and CGRP mAbs show effectiveness and are well tolerated for migraine prevention in older adults. Given the growing ageing population and their unique therapeutic needs, proactive migraine management in older migraine patients with injection-based and oral preventive is essential.

Abstract

Hypertrophic scars and keloids are fibroproliferative disorders arising from aberrant wound healing, often leading to aesthetic disfigurement, functional impairment, and psychosocial burden. Intralesional therapies remain a mainstay of treatment, yet the comparative efficacy and recurrence profiles of different agents have not been definitively established. We conducted a systematic search of PubMed (National Institutes of Health, Bethesda, MD), Cochrane Library (Wiley, Hoboken, NJ), US National Institutes of Health Ongoing Trials Register, EMBASE (Elsevier, Amsterdam, the Netherlands), and Google Scholar (Alphabet, Inc., Mountain View, CA) from inception through May 2025, restricted to English-language publications, to identify randomized controlled trials comparing 2 or more intralesional treatments for hypertrophic scars or keloids. Twenty-four eligible trials were included in a frequentist random-effects network meta-analysis integrating direct and indirect comparisons. Pooled estimates demonstrated that triamcinolone acetonide combined with 5-fluorouracil (TAC + 5-FU) achieved the most consistent improvements in treatment efficacy and recurrence control. Botulinum toxin A (BTA) ranked highest in treatment response but did not significantly reduce recurrence risk. Verapamil was associated with significantly lower efficacy compared with TAC, whereas bleomycin and 5-FU monotherapies provided intermediate outcomes without statistical superiority. Overall, TAC + 5-FU offered the most favorable balance between efficacy and recurrence reduction, whereas BTA showed strong response efficacy. These findings provide a comprehensive synthesis of intralesional therapies for hypertrophic scars and keloids, support the consideration of combination regimens in scar management, and underscore the need for further well-designed head-to-head trials with standardized endpoints to refine individualized treatment strategies. Level of Evidence: 3 (Therapeutic).

Abstract

DaxibotulinumtoxinA for injection (DAXI), the first long-acting botulinum toxin (BoNT) type A, is FDA approved for cervical dystonia (CD). DAXI's novel formulation, which includes a custom-engineered peptide, is designed to provide an extended duration of clinical benefit.

Abstract

Pain in patients with leg ulcers is common and there is a need for effective treatments. The analgesic effects of botulinum neurotoxin A (BTX-A) have been well-documented and this exploratory study primarily investigated its analgesic effect in patients with leg ulcers.

Abstract

OnabotulinumtoxinA (onabotA), a Botulinum neurotoxin type A (BoNT/A), is an effective treatment for chronic migraine, but its direct mechanism of action on human sensory neurons has not been fully elucidated. While rodent studies on dorsal root ganglion (DRG) and trigeminal ganglion (TG) show that BoNT/A inhibits neurotransmission, including calcitonin gene-related peptide (CGRP/CALCA) release, by cleaving synaptosomal-associated protein 25 (SNAP-25), only one previous study has assessed its effect on human DRG neurons. The objective of this study was to understand the mechanism of action of BoNT/A in cultured human sensory neurons and assess, using RNA sequencing, the transcriptomic consequences of BoNT/A treatment. Using DRGs obtained from organ donors, the expression of key targets, including synaptic vesicle glycoprotein 2C (SV2C), SNAP25, & CALCA, was validated by mining existing transcriptomic datasets as well as immunohistochemistry. Cultured dissociated human DRG neurons treated with BoNT/A were used to examine cleavage of SNAP25, release of CGRP, and transcriptomic changes after BoNT/A treatment. SV2C was found to be widely expressed in human DRG neurons in a pattern that completely overlapped with CGRP expression. Consistent with this finding, BoNT/A disrupted soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complexes in human DRG neurons as demonstrated by SNAP-25 cleavage in most somatosensory neurons and a reduction in capsaicin-evoked CGRP release, indicating impaired vesicle fusion. Moreover, bulk RNA sequencing experiments revealed downregulated expression of a large subset of genes responsible for neurotransmitter and neuropeptide release from neurons, suggesting a novel mechanism through which BoNT/A regulates neurotransmission. These results provide new insight into the molecular mechanisms by which BoNT/A may exert its pain-relieving effects in humans.

Abstract

Cardiac hypertrophy is a common adaptation to cardiovascular stress and often a prelude to heart failure. We examined how S-palmitoylation of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), impacts cardiomyocyte stress signaling. Mutation of the Cys-178 palmitoylation site impaired activation of Rac1 when overexpressed in cardiomyocytes. Cardiomyocyte-specific Rac1 conditional knockin (Rac1cKI) mice expressing a Rac1C178S mutant protein exhibited normal cardiac structure and function but developed more severe cardiac hypertrophy in response to angiotensin II (AngII) infusion, cardiomyocyte-specific overexpression of AngII type 1 receptor (AT1R), and cardiac pressure overload. Moreover, pressure overload and AT1R overexpression evoked cardiac failure phenotypes in Rac1cKI mice not observed in controls. Mechanistically, Rac1cKI hearts and cardiomyocytes genetically resistant to Rac1 S-palmitoylation had a profound increase in protein kinase A (PKA) substrate phosphorylation in response to acute β-adrenergic stimulation, as did Rac1cKI hearts subjected to chronic AngII treatment, AT1R overexpression, or pressure overload that correlates with more advanced heart failure phenotypes. This was not associated with increased PKA enzymatic activity, suggesting potential deficits in phosphatase activity at PKA-regulated phospho-sites. Taken together, this study suggests Rac1 S-palmitoylation dampens adrenergic drive and PKA-dependent modulation of the phospho-proteome in response to cardiovascular stress, revealing essential functions for S-acylated Rac1 in cardiac adaptation.

Abstract

Post traumatic headache is a common condition that can be managed with pharmacologic interventions or analgesic procedures; however, most evidence is derived from patients with mild trauma, leaving a large gap with regard to patients with moderate or severe trauma who present complex pain. Botulinum toxin plays an increasingly important role in pain management. This neurotoxin acts on different receptors, ranging from TRPV1 (transient receptor potential vanilloid type 1) to CGRP (calcitonin gene-related peptide). This is the first case report of the use of perineural botulinum toxin in a patient with moderate post-traumatic headache who responded poorly to standard interventional measures.