targeted-toxins

Metz M, Kolkhir P, Altrichter S, Siebenhaar F, Levi-Schaffer F, Youngblood BA, Church MK, Maurer M (2023) Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases. Allergy doi: 10.1111/all.15850 PMID: 37605867

Objective: Authors review the role of mast cells (MC) in the pathogenesis of chronic urticaria (CU), explore current therapeutic strategies, and introduce the concept of MC silencing as a strategy to block activation of MCs without eliciting immunosuppressive adverse effects.

Summary: CU is a MC-dependent disease with limited therapeutic options. Current strategies are directed at inhibiting IgE-mediated activation of MCs. MC depletion or silencing strategies are being developed to overcome limitations of singularly targeted agents. MC silencers, such as monoclonal antibodies that engage inhibitory receptor like sialic acid-binding immunoglobulin-like lectin8 (Siglec-8) have reached preclinical stages of development. Siglecs have been shown to be internalized upon antibody engagement, such as Siglec-8, and is being used to deplete MCs via conjugating saporin to the internalizing Siglec-8 antibody to cause cell death in human mast cells.

Usage: Usage: Anti-Siglec-8 (2C4)-SAP was used at 2.5 µg/ml to eliminate eosinophils and at 1.25 µg/ml to eliminate the HMC-1.2 human mast cell line.

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

See Also:

• 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.

Dobryakova YV, Gerasimov K, Spivak YS, Korotkova T, Koryagina A, Deryabina A, Markevich VA, Bolshakov AP (2023) The induction of long-term potentiation by medial septum activation under urethane anesthesia can alter gene expression in the hippocampus. Int J Mol Sci 24(16):12970. doi: 10.3390/ijms241612970 PMID: 37629149

Objective: To study changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus.

Summary: The data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.

Usage: Injection into the medial septum area (MSA) at a rate of 0.2μL/min. The drug was infused at a concentration of 1.5μg/per rat.

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

Jorgensen MD (2023) Designing coiled-coil peptide materials for biomedical applications. Purdue University Thesis.

Objective: Using saporin [PR-01] containing hydrogel to target and eliminate cancer cells.

Summary: Hydrogels can bind molecular cargo and be used to shuttle cytotoxic drugs across the body. Using a pH-responsive hyaluronic acid nanogel containing saporin, cancer cells with overexpressed CD44 receptor are eliminated.

Related Products: Saporin (Cat. #PR-01), Anti-CD44-SAP (Cat. #IT-72)

See Also:

• Ding L, Jiang Y, Zhang J, Klok HA, Zhong Z (2018) pH-Sensitive Coiled-Coil Peptide-Cross-Linked Hyaluronic Acid Nanogels: Synthesis and Targeted Intracellular Protein Delivery to CD44 Positive Cancer Cells. Biomacromolecules 19(2):555-562. doi: 10.1021/acs.biomac.7b01664 PMID: 29284258

Zhang H, Zhu Y, Chen S, Deng K, Zheng M, Zeng Z, Wang Q, Cai H, Lu Z (2023) Autonomic nerve and its modulation approaches for heart failure. Brain & Heart 1(2):0913. doi: 10.36922/bh.0913

Objective: Authors review neural modulation approaches that can assist in the management of heart failure.

Summary: The autonomic nervous system governs the heart’s neurological regulation through opposing functions of its sympathetic and parasympathetic components. Potential treatments for heart failure include inhibiting the sympathetic nerve’s overactivity and restoring parasympathetic activity in the heart. CTB-SAP was used to ablate cardiac sympathetic neurons via retrograde transport on stellate ganglion neurons.

Usage: CTB-SAP was injected into the right superior vervical ganglion of adult male Sprague-Dawley rats (50 ug/rat).

Related Products: CTB-SAP (Cat. #IT-14)

See Also:

• Llewellyn-Smith IJ et al. Retrogradely transported CTB-saporin kills sympathetic preganglionic neurons. Neuroreport 10(2):307-312, 1999.

Canarutto D, Omer Javed A, Pedrazzani G, Ferrari S, Naldini L (2023) Mobilization-based engraftment of haematopoietic stem cells: a new perspective for chemotherapy-free gene therapy and transplantation. Br Med Bull ldad017. doi: 10.1093/bmb/ldad017 PMID: 37460391

Objective: The authors review alternative chemotherapy-free approaches to niche voidance that could replace conventional regimens and alleviate the morbidity of the procedure.

Summary: In haematopoietic stem cell transplantation (HSCT), haematopoietic stem cells (HSCs) from a healthy donor replace the patient’s. Ex vivo HSC gene therapy (HSC GT) is a form of HSCT in which HSCs are genetically modified before infusion, to generate a progeny of gene-modified cells. In HSCT and HSC-GT, chemotherapy is administered before infusion to free space in the bone marrow niche, which is required for the engraftment of infused cells. One approach reviewed by the authors involves Anti-CD45-SAP. The conjugate was shown to clear the white blood cell compartment. Administration into mice prior to HSCT resulted in comparable haematopoietic reconstitution as total body irradiation, with less side effects (Palchaudhuri R. et al, 2016) and faster T-cell repopulation likely due to sparing radio damage to the thymic stroma (Schiroli G et al., 2017).

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

See Also:

• Palchaudhuri R et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-745, 2016.
• Schiroli G et al. Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Sci Transl Med 9(411):eaan0820, 2017.

Akmese C, Sevinc C, Halim S, Unal G (2023) Differential role of GABaergic and cholinergic ventral pallidal neurons in behavioral despair, conditioned fear memory and active coping. Prog Neuropsychopharmacol Biol Psychiatry 125:110760. doi: 10.1016/j.pnpbp.2023.110760 PMID: 37031946

Objective: To investigate the role of the ventral pallidum (VP) in regulating the brain’s reward circuitry in appetitive behaviors and emotional regulation through GABAergic and Cholinergic lesions.

Summary: Using GAT1-SAP (GABAergic) or 192-IgG-SAP (cholinergic), injections were made into the VP to eliminate neurons in rats. These lesioned rats were subjected to fear conditioning tests, and it was shown that the VP may contribute to emotion regulation by suppressing active coping and promoting species-specific passive behaviors.

Usage: Bilateral injections of GAT1-SAP (325 ng/μl, 0.5 μl volume, 0.1 μl/min), 192-IgG-SAP (500 ng/μl in PBS, 0.5 μl volume, 0.1μl/min), or PBS (0.5 μl volume, 0.1 μl/min) into the Ventral Pallidum.

Related Products: GAT1-SAP (Cat. #IT-32), 192-IgG-SAP (Cat. #IT-01)

Low ZXB, Lee XR, Soga T, Goh BH, Alex D, Kumari Y (2023) Cannabinoids: Emerging sleep modulator. Biomed Pharmacother 165:115102. doi: 10.1016/j.biopha.2023.115102 PMID: 37406510

Objective: To review the modulation of sleep by cannabinoids and the endocannabinoid system.

Summary: This review article discusses the role of cannabinoids, including endocannabinoids like anandamide and phytocannabinoids like THC and CBD, in regulating the sleep-wake cycle. The authors review evidence that cannabinoids act on areas of the brain involved in promoting sleep, like the ventrolateral preoptic nucleus, and inhibit wake-promoting areas, like the locus coeruleus.

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

Kim JS, Williams KC, Kirkland RA, Schade R, Freeman KG, Cawthon CR, Rautmann AW, Smith JM, Edwards GL, Glenn TC, Holmes PV, de Lartigue G, de La Serre CB (2023) The gut-brain axis mediates bacterial driven modulation of reward signaling. Mol Metab 26:101764. doi: 10.1016/j.molmet.2023.101764 PMID: 37380023

Objective: To investigate the role of gut microbiota and vagal signaling in modulating brain dopamine reward pathways and appetitive feeding behavior.

Summary: The study found that high-fat diet and transfer of high-fat microbiota to germ-free rats reduced dopamine signaling and motivated feeding behavior compared to chow-fed and low-fat microbiota groups. Vagal deafferentation restored dopamine signaling and feeding motivation in high-fat microbiota rats, indicating gut bacteria signals that dampen reward are vagally mediated.

Usage: Animals were injected bilaterally into the nodose ganglion with either Saporin or CCK-SAP. A pulled glass micropipette containing either CCK-SAP (240 ng/ml in 0.1 M phosphate buffer) or SAP alone was inserted under the sheath of the cervical vagus and into the NG, the injection was done with a pressure-injector into two sites (one proximal and one distal, total volume, 1 µl).

Related Products: CCK-SAP (Cat. #IT-31), Saporin (Cat. #PR-01)

Zhou Q, Zheng Z, Wang X, Li W, Wang L, Yin C, Zhang Q, Wang Q (2023) taVNS alleviates sevoflurane-induced cognitive dysfunction in aged rats via activating basal forebrain cholinergic neurons. Neurochem Res 48(6):18481863. doi: 10.1007/s11064-023-03871-6 PMID: 36729311

Objective: To investigate if Sevoflurane, an inhalation anesthetic, inhibits cholinergic pathways that induce neuronal death and neuroinflammation, ultimately leading to Postoperative cognitive dysfunction.

Summary: Study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Usage: 192-IgG-SAP (IT-01) selectively lesioned cholinergic neurons in the basal forebrain.

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

Souza GMPR, Stornetta DS, Shi Y, Lim E, Berry FE, Bayliss DA, Abbott SBG (2023) Neuromedin B-expressing neurons in the retrotrapezoid nucleus regulate respiratory homeostasis and promote stable breathing in adult mice. J Neurosci JN-RM-0386-23. doi: 10.1523/JNEUROSCI.0386-23.2023 PMID: 37290937

Objective: To develop a transgenic mouse model and demonstrate that retrotrapezoid nucleus (RTN) neurons are fundamental for respiratory homeostasis and mediate the stimulatory effects of CO2 on breathing.

Summary: This study uses a transgenic Nmb-Cre mouse model to demonstrate that RTNNmb neurons are crucial for CO2-dependent breathing in mice. It provides evidence that these neurons play a key role in respiratory homeostasis and might be linked to sleep-disordered breathing in humans. Cre-dependent cell ablation and optogenetics show RTNNmb neurons’ essential function in mediating the hypercapnic ventilatory response, highlighting the importance of these neurons in maintaining eupneic breathing.

Usage: This publication references the use of SSP-SAP (IT-11) to target RTN neurons.

Related Products: SSP-SAP (Cat. #IT-11)

See Also:

• Takakura AC et al. Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats. Exp Physiol 99(3):571-585, 2014.