targeted-toxins

Jiang H, Cui H, Chen M, Li F, Shen X, Guo CJ, Hoekel GE, Zhu Y, Han L, Wu K, Holtzman MJ, Liu Q (2024) Divergent sensory pathways of sneezing and coughing. Cell 187(21):5981-5997. doi: 10.1016/j.cell.2024.08.009 PMID: 39243765

Objective: To study the difference in sensory receptors and neurotransmission/modulation mechanisms between sneezing and coughing.

Summary: Sneezing and coughing are frequently associated with allergies and respiratory viral infections and it’s assumed both involve common sensory receptors and neurotransmission mechanisms. The author’s work show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11+MrgprA3−) mediates sneezing. Although this same population innervates the trachea, it does not mediate coughing, and instead, a distinct sensory population (somatostatin SST) mediates coughing but not sneezing. NMB-SAP was used to ablate neruomedin B (NMB) receptor expressing and nucleus tractus solitarius (NTS) neurons. Deletion of these neurons did not affect the coughing responses to Ly344864 and IL-31 (agonists to SST neurons) suggesting that NMB-sensitive NTS neurons do not mediate coughing.

Usage: Neuronal ablation by SST-saporin and NMB-saporin. SST-saporin was made by mixing biotin-labeled somatostatin and Streptavidin-ZAP (IT-27) at a 1:1 molar ratio at room temperature for 20 minutes. SST-Saporin (10 μM, 50 nL), NMB-saporin (#IT-70; 50 ng in 50 nL) or Blank-SAP (#IT-21; 10 μM in 50 nL or 50 ng in 50 nL) was injected into the NTS region.

Related Products: Streptavidin-ZAP (Cat. #IT-27), NMB-SAP (Cat. #IT-70), Blank-SAP (Cat. #IT-21)

Limonta P, Chiaramonte R, Casati L (2024) Unveiling the dynamic interplay between cancer stem cells and the tumor microenvironment in melanoma: Implications for novel therapeutic strategies. Cancers (Basel) 16(16):2861. doi: 10.3390/cancers16162861 PMID: 39199632

Objective: To review the bidirectional communication between melanoma cancer stem cells (CSCs) and the tumor microenvironment, highlighting its role in drug resistance and tumor relapse.

Summary: Melanoma CSCs evade immune surveillance and recruit immune cells with immunosuppressive and tumor-promoting properties, establishing a supportive microenvironment. They also transfer stemness and aggressive traits to neighboring non-CSCs, driving tumor progression and metastasis. Targeting these interactions may offer novel therapeutic strategies for combating melanoma.

Usage: This review publication highlights the usage of Anti-CD271-SAP and CD133-SAP in previous publications.

Related Products: ME20.4-SAP (Cat. #IT-15), Anti-CD133-SAP (Cat. #IT-82), Saporin (Cat. #PR-01)

See Also:

• Ngo M et al. Antibody therapy targeting CD47 and CD271 effectively suppresses melanoma metastasis in patient-derived xenografts. Cell Rep 16:1701-1716, 2016.
• Bostad M et al. Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization – A minimally invasive cancer stem cell-targeting strategy. J Control Release 206:37-48, 2015.

Coutinho EA, Esparza LA, Steffen PH, Liaw R, Bolleddu S, Kauffman AS (2024) Selective depletion of kisspeptin neurons in the hypothalamic arcuate nucleus in early juvenile life reduces pubertal LH secretion and delays puberty onset in mice. FASEB J 28(19):e70078. doi: 10.1096/fj.202401696R PMID: 39377760

Objective: To investigate the specific kisspeptin population timing pubertal onset.

Summary: This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes.

Usage: See also these studies where ~70% of ARC kisspeptin (KNDy) neurons were selectively ablated in rats using NKB-SAP (IT-63).

Related Products: NKB-SAP (Cat. #IT-63)

See Also:

• Mittelman-Smith MA et al. Arcuate kisspeptin/neurokinin b/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 153(6):2800-2812 , 2012 .
• Helena C et al. KNDy neurons modulate the magnitude of the steroid-induced luteinizing hormone surges in ovariectomized rats. Endocrinology 156:4200-4213, 2015.
• Mittelman-Smith M et al. Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced LH surge in female rats. Endocrinology 157:2015-2027, 2016.
• Campideli-Santana AC et al. Partial loss of arcuate kisspeptin neurons in female rats stimulates luteinizing hormone and decreases prolactin secretion induced by estradiol. J Neuroendocrinol 34(11):e13204, 2022.

Lusk S, Moushey AM, Li A, Ray R (2024) Exaggerated postnatal surge of orexin neurons and the effects of elimination of excess orexin on blood pressure and exaggerated chemoreflex in spontaneously hypertensive rats. Front Physiol 15:1341649. doi: 10.3389/fphys.2024.1341649 PMID: 39469444

Objective: To investigate whether an increase in postnatal neurogenesis of orexin (OX) neurons in spontaneously hypertensive rats (SHRs) precedes and contributes to elevated mean arterial pressure (MAP) and heightened responses to elevated CO2 (hypercapnia) during development.

Summary: Postnatal increase in OX neurons may be essential for the development of higher MAP and an exaggerated chemoreflex (the body’s response to CO2) in SHRs. Targeting the overactive OX system could provide a potential therapeutic strategy during the early stages of hypertension development.

Usage: Orexin-SAP (0.5 μL, 90 ng/μL) was injected into the hypothalamus to eliminate excess OX neurons and study their effect on elevated MAP and exaggerated chemoreflex responses in adult SHRs.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Doucette L, Turnbill V, Carlin K, Cavanagh A, Sollinger B, Kuter N, Flock DL, Robinson S, Chavez-Valdez R, Jantzie L, Martin LJ, Northington FJ (2024) Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer’s disease-related genes in mice. Neurobiol Dis 200:106629. doi: 10.1016/j.nbd.2024.106629 PMID: 39111704

Objective: Authors hypothesized that neocortical damage caused by neonatal Hypoxic-ischemic (HI) in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer’s disease.

Summary: Simple ChAT+axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings. In contrast, complex ChAT+neuritic clusters (NC) occurred only in Tg mice. The abundance of ChAT+ clusters in specific regions correlated with decreased Visual discrimination. This finding aligns with data that a highly specific cholinergic immunotoxin (mu p75-SAP) in the APP/PS1 mouse model worsens cognitive impairment, and the cognitive impairment appears earlier

Related Products: mu p75-SAP (Cat. #IT-16)

See Also:

• Ramos-Rodriguez JJ et al. Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in app/ps1 mice. J Neuropathol Exp Neurol 72(4):272-285, 2013.

O’Sullivan JA, Youngblood BA, Schleimer RP, Bochner BS (2024) Siglecs as potential targets of therapy in human mast cell- and/or eosinophil-associated diseases. Semin Immunol 69:101799. doi: 10.1016/j.smim.2023.101799 PMID: 37413923

Objective: To review a subset of Siglecs and their various endogenous or synthetic sialoside ligands that regulate eosinophil and mast cell function and survival.

Summary: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are vertebrate glycan-binding cell-surface proteins. Many Siglecs mediate cellular inhibitory activity and are of interest as part of a strategy to therapeutically lessen unwanted cellular responses. Human eosinophils and mast cells express overlapping but distinct patterns of Siglecs, and certain Siglecs have become the focus of novel therapies for allergic and other eosinophil and mast cell-related diseases.

Usage: Saporin in conjunction with CD22 glycomimetic ligand BPCNeuAc leads to cells death induction in a ligand-dependent manner on B-lymphoma cells (Collins et al.). Incubation with anti-Siglec-8 monoclonal antibody conjugated to saporin led to the death of malignant mast cells and eosinophils (O’Sullivan et al.)

Related Products: Saporin (Cat. #PR-01)

See Also:

• Collins BE, Blixt O, Han S, Duong B, Li H, Nathan JK, Bovin N, Paulson JC (2006) High-affinity ligand probes of CD22 overcome the threshold set by cis ligands to allow for binding, endocytosis, and killing of B cells. J Immunol 177(5):2994-3003. doi: 10.4049/jimmunol.177.5.2994 PMID: 16920935
• O’Sullivan J et al. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e1777, 2018.

la Fleur SE, Blancas-Velazquez AS, Stenvers DJ, Kalsbeek A (2024) Circadian influences on feeding behavior. Nauropharmacology 256:110007. doi: 10.1016/j.neuropharm.2024.110007 PMID: 38795953

Objective: To review the effect of deletion of different clock genes on feeding behavior.

Summary: The most prominent effect on feeding behavior has been observed in Clock mutants, where as deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Damaging leptin-sensitive cells within the ARC using saporin-leptin injections (reducing the number of POMC and AgRP cells) induced a-rhythmicity in feeding behavior when animals were held either in a light-dark rhythm or continuous darkness, providing evidence that leptin-sensitive cells of the ARC are important for circadian feeding rhythmicity.

Related Products: Leptin-SAP (Cat. #IT-47)

See Also:

• Li AJ et al. Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am J Physiol Regul Integr Comp Physiol 302(11):R1313-26, 2012.

Dai SP, Yang CC, Chin Y, Sun WH (2024) T cell death-associated gene 8-mediated distinct signaling pathways modulate the early and late phases of neuropathic pain. iScience 27(10):110955. doi: 10.1016/j.isci.2024.110955 PMID: 39381739

Objective: To elucidate how T cell death-associated gene 8 (TDAG8)-mediated signaling modulates neuron activities in a mouse model of chronic constriction injury-induced neuropathic pain.

Summary: TDAG8 participated alone in mechanical allodynia induced by constriction injury. TDAG8-Nav1.8 signaling in small-diameter isolectin B4-positive [IB4(+)] neurons initiate mechanical allodynia; it also modulated substance P release from IB4(-) neurons to facilitate the development of early mechanical allodynia. TDAG8-mediated signaling increased medium-to large-diameter IB4(-) neuron activity to maintain late mechanical allodynia; it also modulated substance P release in soma to reduce satellite glial number and Nav1.7 expression, thus attenuating chronic mechanical allodynia.

Usage: Mice were intrathecally injected with IB4-saporin (IB4-SAP, 0.06 mg/mL) or Saporin (0.06 mg/mL)

Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)

Penna S, Zecchillo A, Di Verniere M, Fontana E, Iannello V, Palagano E, Mantero S, Cappelleri A, Rizzoli E, Santi L, Crisafulli L, Filibian M, Forlino A, Basso-Ricci L, Scala S, Scanziani E, Schinke T, Ficara F, Sobacchi C, Villa A, Capo V (2024) Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning. Front Endocrinol (Lausanne) 15:1450349. doi: 10.3389/fendo.2024.1450349 PMID: 39314524

Objective: To investigate whether gene therapy (GT) could minimize the immune-mediated complications of allogeneic hematopoietic stem cell transplantation (HSCT) and offer a prompt treatment.

Summary: Authors showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis and that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity.

Usage: Recipient oc/oc mice were conditioned by CD45-SAP injections or total body irradiation (IRR)

Related Products: Anti-CD45.2-SAP (Cat. #IT-91)

Moschonas EH (2024) Cholinergic neurotransmission during performance of a sustained attention task after traumatic brain injury. Univ Pittsburgh School of Medicine Thesis.

Objective: To elucidate the role of basal forebrain cholinergic neurons (BFCNs) in mediating attentional performance and ACh efflux

Summary: Saporin-induced lesions to the nbM impaired signal detection accuracy during performance of the Sustained Attention Task (SAT). Similarly, in tasks of divided attention that involve both auditory and visual stimuli, cholinergic lesions to the nbM result in prolonged response times during bimodal trials compared to unimodal trials, which involve a single sensory modality.

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• McGaughy J et al. Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112(6):1519-1525, 1998.
• McGaughy J et al. The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins. Behav Brain Res 115:251-263, 2000.
• Dalley JW et al. Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-Saporin-induced lesions of the medial prefrontal cortex. Cereb Cortex 14(8):922-932, 2004.
• Chudasama Y et al. Cholinergic modulation of visual attention and working memory: Dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine. Learn Mem 11(1):78-86, 2004.
• Botly LC et al. Cholinergic deafferentation of the neocortex using 192 IgG-saporin impairs feature binding in rats. J Neurosci 29:4120-4130, 2009.
• Butt AE et al. Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255, 2002.
• Butt AE et al. Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255, 2002.