scholarly journals New Engineered-Botulinum Toxins Inhibit the Release of Pain-Related Mediators

2019 ◽  
Vol 21 (1) ◽  
pp. 262 ◽  
Author(s):  
Minhong Tang ◽  
Jianghui Meng ◽  
Jiafu Wang
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Unmet Need ◽  
New Approach ◽  
P Release ◽  
Effective Delivery ◽  
Ifn Γ ◽  
Cgrp Receptor Antagonist ◽  
Substance P Release ◽  
Promising Avenue

Targeted delivery of potent inhibitor of cytokine/pain-mediator into inflammatory or pain-sensing cells is a promising avenue for treating chronic pain, a world-wide major healthcare burden. An unmet need exists for a specific and effective delivery strategy. Herein, we describe a new approach using sortase to site-specifically ligate a non-toxic botulinum neurotoxin D (BoNT/D) core-therapeutic (synaptobrevin-cleaving protease and translocation domains) to cell-specific targeting ligands. An engineered core-therapeutic was efficiently ligated to IL-1β ligand within minutes. The resultant conjugate specifically entered into cultured murine primary macrophages, cleaved synaptobrevin 3 and inhibited LPS/IFN-γ evoked IL-6 release. Likewise, a CGRP receptor antagonist ligand delivered BoNT/D protease into sensory neurons and inhibited K+-evoked substance P release. As cytokines and neuropeptides are major regulators of inflammation and pain, blocking their release by novel engineered inhibitors highlights their therapeutic potential. Our report describes a new and widely-applicable strategy for the production of targeted bio-therapeutics for numerous chronic diseases.

scholarly journals Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Azmat Ali Khan ◽  
Amer M. Alanazi ◽  
Mumtaz Jabeen ◽  
Arun Chauhan ◽  
Mohammad Azam Ansari
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Survivin Expression ◽  
Significant Inhibition ◽  
Target Cells ◽  
Specific Gene ◽  
Antitumor Potential ◽  
Effective Delivery ◽  
Selective Delivery ◽  
Interfering Rna

Abstract Short interfering RNA (siRNA) possesses special ability of silencing specific gene. To increase siRNA stability, transportation and its uptake by tumor cells, effective delivery to the appropriate target cells is a major challenge of siRNA-based therapy. In the present study, an effective, safe and biocompatible survivin siRNA encapsulated, GalNAc decorated PEGylated PLGA nanoconjugates (NCs) viz., GalNAc@PEG@siRNA-PLGA were engineered and their synergistic antitumor efficacy was evaluated for targeted delivery in HCC bearing experimental mice. GalNAc@PEG@siRNA-PLGA NCs were characterized for size, bioavailability, toxicity and biocompatibility. Their antitumor potential was evaluated considering gene silencing, apoptosis, histopathology and survival of treated mice. Exceptional accumulation of hepatocytes, reduction in survivin expression and prominent regression in tumor size confirmed the ASGPR-mediated uptake of ligand-anchored NCs and silencing of survivin gene in a targeted manner. Increased DNA fragmentation and potential modulation of caspase-3, Bax and Bcl-2 factors specified the induction of apoptosis that helped in significant inhibition of HCC progression. The potential synchronous and tumor selective delivery of versatile NCs indicated the effective payloads towards the target site, increased apoptosis in cancer cells and improved survival of treated animals.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

scholarly journals Skullcapflavone II Suppresses TNF-α/IFN-γ-Induced TARC, MDC, and CTSS Production in HaCaT Cells

2021 ◽  
Vol 22 (12) ◽  
pp. 6428
Author(s):  
Hanon Lee ◽  
Dong Hun Lee ◽  
Jang-Hee Oh ◽  
Jin Ho Chung
Keyword(s):  
P38 Mapk ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Mapk Signaling ◽  
Hacat Cells ◽  
Protein Levels ◽  
Tnf Α ◽  
Ifn Γ ◽  
Mapk Signaling Pathways ◽  
Pro Inflammatory Cytokines

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis, has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.

scholarly journals CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daekwon Bae ◽  
Ji-Young Lee ◽  
Nina Ha ◽  
Jinsol Park ◽  
Jiyeon Baek ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Autoimmune Encephalitis ◽  
Selective Inhibitor ◽  
Therapeutic Effects ◽  
Treatment Regimens ◽  
Ifn Γ ◽  
Experimental Autoimmune

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

scholarly journals Redox Responsive Pluronic Micelle Mediated Delivery of Functional siRNA: A Modular Nano-Assembly for Targeted Delivery

2021 ◽  
Author(s):  
Sandeep Kadekar ◽  
Ganesh N. Nawale ◽  
Vignesh Kumar Rangasami ◽  
Vadim Le Joncour ◽  
Pirjo Laakkonen ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Unmet Need ◽  
Short Interfering Rna ◽  
Site Specific ◽  
Redox Responsive ◽  
Interfering Rna

There is an unmet need to develop strategies that allow site-specific delivery of short interfering RNA (siRNA) without any associated toxicity. To address this challenge, we have developed a novel...

Calcium and capsaicin- induced substance P release from peripheral terminals of primary sensory neurons

1988 ◽  
Vol 22 (1-2) ◽  
pp. 117 ◽  
Author(s):  
C.A. Maggi ◽  
P. Santicioli ◽  
P. Geppetti ◽  
R. Patacchini ◽  
E. Del Bianco ◽  
...  
Keyword(s):  
Substance P ◽  
Sensory Neurons ◽  
Primary Sensory Neurons ◽  
P Release ◽  
Substance P Release

scholarly journals Sufentanil, Morphine, Met-enkephalin, and k-Agonist (U-50,488H) Inhibit Substance P Release from Primary Sensory Neurons

1989 ◽  
Vol 70 (4) ◽  
pp. 672-677 ◽  
Author(s):  
H. Ming Chang ◽  
Charles B. Berde ◽  
George G. Holz ◽  
Grieg F. Steward ◽  
Richard M. Kream
Keyword(s):  
Substance P ◽  
Sensory Neurons ◽  
Primary Sensory Neurons ◽  
P Release ◽  
Inhibit Substance ◽  
Substance P Release

scholarly journals Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

1995 ◽  
Vol 95 (5) ◽  
pp. 2359-2366 ◽  
Author(s):  
A Garland ◽  
J E Jordan ◽  
J Necheles ◽  
L E Alger ◽  
M M Scully ◽  
...  
Keyword(s):  
Substance P ◽  
Primary Culture ◽  
P Release ◽  
C Fiber ◽  
Substance P Release

scholarly journals Effects of General Anesthetics on Substance P Release and c-Fos Expression in the Spinal Dorsal Horn

2013 ◽  
Vol 119 (2) ◽  
pp. 433-442 ◽  
Author(s):  
Toshifumi Takasusuki ◽  
Shigeki Yamaguchi ◽  
Shinsuke Hamaguchi ◽  
Tony L. Yaksh
Keyword(s):  
Nitrous Oxide ◽  
Substance P ◽  
Dorsal Horn ◽  
Receptor Internalization ◽  
General Anesthetics ◽  
Neurokinin 1 Receptor ◽  
P Release ◽  
Fos Expression ◽  
Neurokinin 1 ◽  
Substance P Release

Abstract Background: The authors examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn. Methods: Rats received saline, propofol (100 mg/kg), pentobarbital (50 mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%), or fentanyl (30 μg/kg). During anesthesia, rats received intraplantar 5% formalin (50 μl) to left hind paw. Ten minutes later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of neurokinin 1 receptor internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 h and c-Fos expression measured. Results: Intraplantar formalin-induced robust neurokinin 1 receptor internalization in ipsilateral dorsal horn (ipsilateral: 54 ± 6% [mean ± SEM], contralateral: 12 ± 2%; P < 0.05; n = 4). Fentanyl, but not propofol, pentobarbital, isoflurane, nor nitrous oxide alone inhibited neurokinin 1 receptor internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced neurokinin 1 receptor internalization (27 ± 3%; P < 0.05; n = 5). All agents reduced c-Fos expression (control: 34 ± 4, fentanyl: 8 ± 2, isoflurane: 12 ± 3, nitrous oxide: 11 ± 2, isoflurane + nitrous oxide: 12 ± 1, pentobarbital: 11 ± 2, propofol: 13 ± 3; P < 0.05; n = 3). Conclusion: General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism that is independent of an effect on small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggest a correlative rationale for the therapeutic use of these anesthetic protocols by blocking nociceptive afferent transmitter release and preventing the initiation of cascade, which is immediately postsynaptic to the primary afferent.

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