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Kawada T, Aoyama M, Matsubara S, Osugi T, Sakai T, Kirimoto S, Nakaoka S, Sugiura Y, Yasuda K, Satake H. Ovarian tachykinin signaling system induces the growth of secondary follicles during the gonadotropin-independent process. J Biol Chem 2025; 301:108375. [PMID: 40043951 PMCID: PMC11999619 DOI: 10.1016/j.jbc.2025.108375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 02/23/2025] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Abstract
Mammalian follicle growth development is mainly regulated by the hypothalamus-pituitary-gonadal axis after puberty. Although pituitary hormones, gonadotropins, are involved in hypothalamus-pituitary-gonadal axis signaling, they are not responsible for the growth of early stage follicles, namely, primordial follicles, primary follicles, and secondary follicles, in both sexually immature and mature individuals. Unlike those of gonadotropin-dependent follicle growth, the specific regulatory factors of gonadotropin-independent follicle growth have yet to be identified. Here, we identified tachykinins (TKs) as inducers of gonadotropin-independent secondary follicle growth. TKs play various roles as neuropeptides or hormones in a wide variety of biological events both in the central nervous system and in peripheral tissues, but a direct effect of TKs on ovarian follicles has yet to investigated. Follicle development was suppressed in sexually immature 3-week-old KO mice of Tac1 gene encoding TKs (substance P and neurokinin A), which is independent of gonadotropins. TKs and their receptors are specifically localized to granulosa cells in mouse secondary follicles. Furthermore, TKs upregulate the prostaglandin (PG) synthase cyclooxygenase 2 via the Janus kinase 1-signal transducers and activators of transcription protein 3 signaling cascade. We also demonstrated that PGE2 and PGF2α are major PGs in the immature ovary, and the secondary follicle growth was enhanced by interaction between PGE2-PGF2α and their receptors, PGE2 receptor localized in the oocyte membrane and PGF2α receptor localized in the oocyte membrane, granulosa cells, and theca cells. Consequently, this study paves the way for exploring gonadotropin-independent early stage follicle growth systems and relevant dysfunctions, including pediatric endocrinological diseases.
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Affiliation(s)
- Tsuyoshi Kawada
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Masato Aoyama
- Department of Chemistry, Biology, and Environmental Science, Faculty of Science, Nara Women's University, Nara, Japan
| | - Shin Matsubara
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Tomohiro Osugi
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Tsubasa Sakai
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Shinji Kirimoto
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Satsuki Nakaoka
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Yuki Sugiura
- Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Yasuda
- Department of Chemistry, Biology, and Environmental Science, Faculty of Science, Nara Women's University, Nara, Japan
| | - Honoo Satake
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan.
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Yook HJ, Lee JH. Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics. Int J Mol Sci 2024; 25:5164. [PMID: 38791201 PMCID: PMC11121340 DOI: 10.3390/ijms25105164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 05/26/2024] Open
Abstract
Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell-neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to the release of inflammatory cytokines and itch-inducing substances. Activated sensory nerve fibers aggravate pruritus by releasing neurotransmitters, perpetuating a vicious cycle of itching and scratching. Traditional treatments often fail, but recent advancements in understanding the inflammatory and itch transmission mechanisms of PN have paved the way for innovative therapeutic approaches, which are explored in this review.
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Affiliation(s)
| | - Ji Hyun Lee
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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English CD, Kazi KJ, Konig I, Ivantsova E, Souders Ii CL, Martyniuk CJ. Exposure to the antineoplastic ifosfamide alters molecular pathways related to cardiovascular function, increases heart rate, and induces hyperactivity in zebrafish (Danio rerio). ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 107:104427. [PMID: 38527598 DOI: 10.1016/j.etap.2024.104427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 03/27/2024]
Abstract
Ifosfamide is an alkylating antineoplastic drug used in chemotherapy, but it is also detected in wastewater. Here, the objectives were to (1) determine teratogenic, cardiotoxic, and mitochondrial toxicity potential of ifosfamide exposure; (2) elucidate mechanisms of toxicity; (3) characterize exposure effects on larval behavior. Survival rate, hatch rate, and morphological deformity incidence were not different amongst treatments following exposure levels up to 1000 µg/L ifosfamide over 7 days. RNA-seq reveled 231 and 93 differentially expressed transcripts in larvae exposed to 1 µg/L and 100 µg/L ifosfamide, respectively. Several gene networks related to vascular resistance, cardiovascular response, and heart rate were affected, consistent with tachycardia observed in exposed embryonic fish. Hyperactivity in larval zebrafish was observed with ifosfamide exposure, potentially associated with dopamine-related gene networks. This study improves ecological risk assessment of antineoplastics by elucidating molecular mechanisms related to ifosfamide toxicity, and to alkylating agents in general.
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Affiliation(s)
- Cole D English
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Kira J Kazi
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Isaac Konig
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA; Department of Chemistry, Federal University of Lavras (UFLA), Minas Gerais, Brazil
| | - Emma Ivantsova
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Christopher L Souders Ii
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Christopher J Martyniuk
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA; UF Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, FL, USA.
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Meng F, Li J, Han X, Li L, Li T, Du X, Cao X, Liang Q, Huang A, Kong F, Zeng X, Bu G. TAC3 regulates GnRH/gonadotropin synthesis in female chickens. Theriogenology 2024; 215:302-311. [PMID: 38128223 DOI: 10.1016/j.theriogenology.2023.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023]
Abstract
Neurokinin B (NKB), a peptide encoded by the tachykinin 3 (TAC3), is critical for reproduction in all studied species. However, its potential roles in birds are less clear. Using the female chicken (c-) as a model, we showed that cTAC3 is composed of five exons with a full-length cDNA of 787 bp, which was predicted to generate the mature NKB peptide containing 10 amino acids. Using cell-based luciferase reporter assays, we demonstrated that cNKB could effectively and specifically activate tachykinin receptor 3 (TACR3) in HEK293 cells, suggesting its physiological function is likely achieved via activating cTACR3 signaling. Notably, cTAC3 and cTACR3 were predominantly and abundantly expressed in the hypothalamus of hens and meanwhile the mRNA expression of cTAC3 was continuously increased during development, suggesting that NKB-TACR3 may emerge as important components of the neuroendocrine reproductive axis. In support, intraperitoneal injection of cNKB could significantly promote hypothalamic cGnRH-Ι, and pituitary cFSHβ and cLHβ expression in female chickens. Surprisingly, cTAC3 and cTACR3 were also expressed in the pituitary gland, and cNKB treatment significantly increased cLHβ and cFSHβ expression in cultured primary pituitary cells, suggesting cNKB can also act directly at the pituitary level to stimulate gonadotropin synthesis. Collectively, our results reveal that cNKB functionally regulate GnRH/gonadotropin synthesis in female chickens.
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Affiliation(s)
- Fengyan Meng
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China.
| | - Jinxuan Li
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Xingfa Han
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Lingyang Li
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Tianyang Li
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Xiaogang Du
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Xiaohan Cao
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Qiuxia Liang
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Anqi Huang
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Fanli Kong
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Xianyin Zeng
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China
| | - Guixian Bu
- College of Life Science, Sichuan Agricultural University, Xinkang Road, Ya'an, 625014, PR China.
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Xiao K, Huang H, Shi X, Shu T, Cheng X, Du H, Yang J. The Effects of Tachykinin1 Gene Products on Prepubertal Dabry's Sturgeon ( Acipenser dabrynus) Pituitary Hormone Secretion and Gene Expression. Animals (Basel) 2024; 14:227. [PMID: 38254396 PMCID: PMC10812735 DOI: 10.3390/ani14020227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
As an ancient and endangered species unique to the Yangtze River in China, the wild population of the Dabry's sturgeon has become scarce. Due to the long time till the first sexual maturity of Dabry's sturgeon, the population of artificially bred Dabry's sturgeon recovered slowly. As a member of the tachykinin family, TAC1 has been reported to have a variety of functions in mammals such as pain control, smooth muscle contraction and reproductive cycle regulation, but the function of Tac1 in fish has been rarely reported. In this study, we synthesized two tac1 gene products, Substance P (SP) and neurokinin A (NKA), and further verified the effect of two tac1 gene products on the secretion of related hormones in the pituitary of Dabry's Sturgeon by intraperitoneal injection and co-culture of primary cells. Expression studies revealed that the newly cloned tac1 were mainly distributed in the hypothalamus and pituitary tissue of the brain. In prepubertal Dabry's sturgeon, this study showed that the two gonadotropins' mRNA levels in pituitary tissue can be significantly increased by SP and NKA through intraperitoneal injection, and the LH protein level in serum was also increased. Further study showed that both NKA and SP could promote the two gonadotropins' mRNA expression in pituitary cells of Dabry's sturgeon. In addition, we explored the optimal dose and time of SP and NKA on pituitary cells is 24 h and over 10 nM. These results, as a whole, suggested that tac1 gene products play an important role in gonadotropin release and gonadal development in prepubertal Dabry's sturgeon.
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Affiliation(s)
- Kan Xiao
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Hongtao Huang
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Xuetao Shi
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Tingting Shu
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Xu Cheng
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Hejun Du
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
| | - Jing Yang
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang 443100, China; (K.X.); (H.H.); (X.S.); (T.S.); (X.C.); (H.D.)
- Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang 443100, China
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6
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Patel B, Koysombat K, Mills EG, Tsoutsouki J, Comninos AN, Abbara A, Dhillo WS. The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B. Endocr Rev 2024; 45:30-68. [PMID: 37467734 PMCID: PMC10765167 DOI: 10.1210/endrev/bnad023] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 06/13/2023] [Accepted: 07/11/2023] [Indexed: 07/21/2023]
Abstract
Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.
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Affiliation(s)
- Bijal Patel
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
| | - Kanyada Koysombat
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, 72 Du Cane Rd, London, W12 0HS, UK
| | - Edouard G Mills
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, 72 Du Cane Rd, London, W12 0HS, UK
| | - Jovanna Tsoutsouki
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
| | - Alexander N Comninos
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, 72 Du Cane Rd, London, W12 0HS, UK
| | - Ali Abbara
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, 72 Du Cane Rd, London, W12 0HS, UK
| | - Waljit S Dhillo
- Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, W12 0NN, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, 72 Du Cane Rd, London, W12 0HS, UK
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Ramzan MH, Shah M, Ramzan F. Neurokinin B Administration Induces Dose Dependent Proliferation of Seminal Vesicles in Adult Rats. Curr Protein Pept Sci 2024; 25:339-352. [PMID: 38243941 DOI: 10.2174/0113892037264538231128072614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/03/2023] [Accepted: 10/16/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Neurokinin B; an endogenous decapeptide, mediates its reproductive physiological actions through gonadotropin releasing hormone. Despite the potential role of Neurokinin B on seminal vesicles, its effects on seminal vesicles in adult male mammals remain elusive. We aimed to investigate the potentials of variable doses of Neurokinin B, its agonist and antagonist on histomorphology and expression of NK3R on seminal vesicles, and secretory activity of seminal vesicles in adult male rats. METHODS Adult male Sprague Dawley rats (n=10 in each group) were administered intraperitoneally with Neurokinin B in three variable doses: 1 μg, 1 ηg and 10 ρg while, Senktide (Neurokinin B agonist) and SB222200 (Neurokinin B antagonist) in 1 μg doses consecutively for 12 days. After 12 days of peptide treatment, half of the animals (n=05) in each group were sacrificed while remaining half (n=05) were kept for another 12 days without any treatment to investigate treatment reversal. Seminal vesicles were dissected and excised tissue was processed for light microscopy, immunohistochemistry and estimation of seminal fructose levels. RESULTS Treatment with Neurokinin B and Senktide significantly increased while SB222200 slightly decrease the seminal vesicles weight, epithelial height and seminal fructose levels as compared to control. Light microscopy revealed increased epithelial height and epithelial folding as compared to control in all Neurokinin B and Senktide treated groups while decreased in SB222200. Effects of various doses of Neurokinin B, Senktide and SB222200 on seminal vesicles weight, epithelial height, seminal fructose levels and histomorphology were reversed when rats were maintained without treatments. Immuno-expression of Neurokinin B shows no change in treatment and reversal groups. CONCLUSION Continuous administration of Neurokinin B and Senktide effect positively while SB222200 have detrimental effects on cellular morphology, epithelial height and seminal fructose levels in seminal vesicles. Effects of peptide treatments depicted a reversal towards control group when rats were kept without any treatment.
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Affiliation(s)
- Muhammad Haris Ramzan
- Department of Physiology, Khyber Medical University Institute of Medical Sciences (KMU-IMS), Kohat 26000, Pakistan
- Department of Physiology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar25100, Pakistan
| | - Mohsin Shah
- Department of Physiology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25100, Pakistan
| | - Faiqah Ramzan
- Department of Animal Sciences, Faculty of Veterinary and Animal Sciences (FVAS), Gomal University, Dera Ismail Khan, 29050, Pakistan
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Rodriguez FD, Covenas R. Association of Neurokinin-1 Receptor Signaling Pathways with Cancer. Curr Med Chem 2024; 31:6460-6486. [PMID: 37594106 DOI: 10.2174/0929867331666230818110812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 06/14/2023] [Accepted: 07/01/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. METHODS This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. CONCLUSION NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.
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Affiliation(s)
- Francisco David Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
| | - Rafael Covenas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, 37007 Salamanca, Spain
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9
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Kumar V, Doshi G. Revolutionizing Infertility Management through Novel Peptide-based Targets. Curr Protein Pept Sci 2024; 25:738-752. [PMID: 38778605 DOI: 10.2174/0113892037304433240430144106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/25/2024]
Abstract
Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory dysfunctions, male infertility, polycystic ovary syndrome, and tubule disease. The remaining 15% have infertility for unknown reasons, including lifestyle and environmental factors. The regulation of the hypothalamic- pituitary-adrenal axis (HPA) is crucial for the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are essential for female reproductive functions. GnRH is the primary reproductive axis regulator. The pattern of GnRH, FSH, and LH release is determined by its pulsatile secretion, which in turn controls endocrine function and gamete maturation in the gonads. Peptides called Kisspeptin (KP), Neurokinin-B (NKB), and Orexin influence both positive and negative feedback modulation of GnRH, FSH, and LH secretion in reproduction. This review article mainly focuses on the historical perspective, isoform, and signaling pathways of KP, NKB, and Orexin novel peptide-based targets including clinical and preclinical studies and having a promising effect in the management of infertility.
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Affiliation(s)
- Vijay Kumar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai 400 056, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai 400 056, India
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10
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Wang F, Zhong W, Yang Q, Zhao W, Liu X, Rao B, Lin X, Zhang J. Distribution and synaptic organization of substance P-like immunoreactive neurons in the mouse retina. Brain Struct Funct 2023; 228:1703-1724. [PMID: 37481742 DOI: 10.1007/s00429-023-02688-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023]
Abstract
Substance P (SP), a neuroprotective peptidergic neurotransmitter, is known to have immunoreactivity (IR) localized to amacrine and/or ganglion cells in a variety of species' retinas, but it has not yet been studied in the mouse retina. Thus, we investigated the distribution and synaptic organization of SP-IR by confocal and electron microscopy immunocytochemistry in the mouse retina. SP-IR was distributed in the inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Most of the SP-IR somas belonged to amacrine cells (2.5% of all) in the INL and their processes stratified into the S1, S3, and S5 layers of the IPL, with the most intense band in the S5 layer. Some SP-IR somas can also be observed in the GCL, which were identified as displaced amacrine cells (82%, 1269/1550) and ganglion cells (18%, 281/1550) by antibodies against AP2α and RBPMS, respectively. Such SP-IR ganglion cells (1.2% of all RGCs) can be further divided into 3 subgroups expressing SP/α-Synuclein (α-Syn), SP/GAD67, and/or SP/GAD67/α-Syn. Possible physiological and pathological roles of these ganglion cells are discussed. Further, electron microscopy evidence demonstrates that SP-IR amacrine cells receive major inputs from other SP-IR amacrine cell processes (146/242 inputs) and output mostly to SP-negative amacrine cell processes (291/673 outputs), suggesting series inhibition among amacrine cells. These results reveal for the first time an explicit distribution, novel ganglion cell features, and synaptic organization of SP-IR in the mouse retina, which is important for the future use of mouse models to study the roles of SP in healthy and diseased (including Parkinson's disease) retinal states.
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Affiliation(s)
- Fenglan Wang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Wenhui Zhong
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qingwen Yang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Wenna Zhao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoqing Liu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Bilin Rao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- Laboratory of Retinal Physiology and Disease, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Xin Lin
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- Laboratory of Retinal Physiology and Disease, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jun Zhang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Laboratory of Retinal Physiology and Disease, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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11
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Safwat A, Helmy A, Gupta A. The Role of Substance P Within Traumatic Brain Injury and Implications for Therapy. J Neurotrauma 2023; 40:1567-1583. [PMID: 37132595 DOI: 10.1089/neu.2022.0510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023] Open
Abstract
This review examines the role of the neuropeptide substance P within the neuroinflammation that follows traumatic brain injury. It examines it in reference to its preferential receptor, the neurokinin-1 receptor, and explores the evidence for antagonism of this receptor in traumatic brain injury with therapeutic intent. Expression of substance P increases following traumatic brain injury. Subsequent binding to the neurokinin-1 receptor results in neurogenic inflammation, a cause of deleterious secondary effects that include an increased intracranial pressure and poor clinical outcome. In several animal models of TBI, neurokinin-1 receptor antagonism has been shown to reduce brain edema and the resultant rise in intracranial pressure. A brief overview of the history of substance P is presented, alongside an exploration into the chemistry of the neuropeptide with a relevance to its functions within the central nervous system. This review summarizes the scientific and clinical rationale for substance P antagonism as a promising therapy for human TBI.
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Affiliation(s)
- Adam Safwat
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Adel Helmy
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Arun Gupta
- Neurosciences Critical Care Unit, Addenbrooke's Hospital, Cambridge, United Kingdom
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12
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Singh A, Lal B, Kumar P, Parhar IS, Millar RP. Role of Neurokinin B in gametogenesis and steroidogenesis of freshwater catfish, Clarias batrachus. Cell Tissue Res 2023; 393:377-391. [PMID: 37278825 DOI: 10.1007/s00441-023-03788-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/12/2023] [Indexed: 06/07/2023]
Abstract
Neurokinin B (NKB), a recently discovered neuropeptide, plays a crucial role in regulating the kiss-GnRH neurons in vertebrate's brain. NKB is also characterized in gonadal tissues; however, its role in gonads is poorly understood. Therefore, in the present study, the effects of NKB on gonadal steroidogenesis and gametogenesis through in vivo and in vitro approaches using NKB antagonist MRK-08 were evaluated. The results suggest that the NKB antagonist decreases the development of advanced ovarian follicles and germ cells in the testis. In addition, MRK-08 further reduces the production of 17β-estradiol in the ovary and testosterone in the testis under both in vivo and in vitro conditions in a dose-dependent manner. Furthermore, the in vitro MRK-08 treatment of gonadal explants attenuated the expression of steroidogenic marker proteins, i.e., StAR, 3β-HSD, and 17β-HSD dose-dependently. Moreover, the MAP kinase proteins, pERK1/2 & ERK1/2 and pAkt & Akt were also downregulated by MRK-08. Thus, the study suggests that NKB downregulates steroidogenesis by modulating the expressions of steroidogenic marker proteins involving ERK1/2 & pERK1/2 and Akt/pAkt signalling pathways. NKB also appears to regulate gametogenesis by regulating gonadal steroidogenesis in the catfish.
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Affiliation(s)
- Ankur Singh
- Fish Endocrinology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, 221005, Varanasi, India
| | - Bechan Lal
- Fish Endocrinology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, 221005, Varanasi, India.
| | - Pankaj Kumar
- Department of Zoology, Rajiv Gandhi University, Rono Hills, Doimukh, Itanagar, Arunachal Pradesh, India
| | - Ishwar S Parhar
- Brain Research Institute, School of Medicine and Health Sciences, Monash University, Sunway Campus, Malaysia
| | - Robert P Millar
- Centre for Neuroendocrinology, Department of Immunology, University of Pretoria, Pretoria and Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa
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13
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Xie Y, Shi X, Xiao K, Zhou L, Shu T, Du H, Yang J, Hu G. Sequences analysis and pituitary actions of tachykinins in Chinese sturgeon (Acipenser sinensis). Gene 2023:147592. [PMID: 37356741 DOI: 10.1016/j.gene.2023.147592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 06/17/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
Tachykinins belong to a large, evolutionarily conserved family of brain/gut peptides that are involved in a variety of physiological functions in mammals, such as reproductive regulation. However, little information was available about tachykinins in ancient fish lineage. In the present study, we firstly identified three tachykinin genes (named tac1, tac3 and tac4) and three neurokinin receptors (named nk1r, nk2r and nk3r) from Chinese sturgeon brain and pituitary. Sequence analysis showed that tac1 encoded substance P (SP) and neurokinin A (NKA), tac3 encoded neurokinin B (NKB) and NKB-related peptide (NKBRP), and tac4 encoded hemokin 1 (HK-1) and hemokin 2 (HK-2), respectively. The luciferase reporter assay results showed that NK1R preferentially selected asSP, NK2R preferentially selected asNKA, and NK3R preferentially selected asNKB. Tissue expression analysis showed that the three tac genes were highly detected in the telencephalon and hypothalamus, whereas nkr genes were widely expressed in peripheral tissues. Spatio-temporal expression analysis showed that all three tac genes were highly expressed in unknown sex individuals. Intraperitoneal injection experiments showed that both asSP and asNKB could stimulate luteinizing hormone (LH) release in Chinese sturgeon serum. At the transcriptional level, asSP and asNKB could significantly reduce pituitary follicle-stimulating hormone beta (fshβ) mRNA expression, but induce pituitary growth hormone (gh) mRNA expression. In addition, estradiol (E2) could stimulate tac3 mRNA expression in hypothalamus. Taken together, this study provided information on the tachykinin family in Chinese sturgeon and demonstrates that asNKB and asSP could be involved in reproductive and growth regulation in pituitary.
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Affiliation(s)
- Yunyi Xie
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Xuetao Shi
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei, 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei, 443100, China
| | - Kan Xiao
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei, 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei, 443100, China
| | - Lingling Zhou
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Tingting Shu
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei, 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei, 443100, China
| | - Hejun Du
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei, 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei, 443100, China
| | - Jing Yang
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei, 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei, 443100, China
| | - Guangfu Hu
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
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14
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Favretti M, Iannuccelli C, Di Franco M. Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions. Int J Mol Sci 2023; 24:10443. [PMID: 37445618 DOI: 10.3390/ijms241310443] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/16/2023] [Accepted: 06/18/2023] [Indexed: 07/15/2023] Open
Abstract
Fibromyalgia is a complex and heterogeneous clinical syndrome, mainly characterized by the presence of widespread pain, possibly associated with a variety of other symptoms. Fibromyalgia can have an extremely negative impact on the psychological, physical and social lives of people affected, sometimes causing patients to experience dramatically impaired quality of life. Nowadays, the diagnosis of fibromyalgia is still clinical, thus favoring diagnostic uncertainties and making its clear identification challenging to establish, especially in primary care centers. These difficulties lead patients to undergo innumerable clinical visits, investigations and specialist consultations, thus increasing their stress, frustration and even dissatisfaction. Unfortunately, research over the last 25 years regarding a specific biomarker for the diagnosis of fibromyalgia has been fruitless. The discovery of a reliable biomarker for fibromyalgia syndrome would be a critical step towards the early identification of this condition, not only reducing patient healthcare utilization and diagnostic test execution but also providing early intervention with guideline-based treatments. This narrative article reviews different metabolite alterations proposed as possible biomarkers for fibromyalgia, focusing on their associations with clinical evidence of pain, and highlights some new, promising areas of research in this context. Nevertheless, none of the analyzed metabolites emerge as sufficiently reliable to be validated as a diagnostic biomarker. Given the complexity of this syndrome, in the future, a panel of biomarkers, including subtype-specific biomarkers, could be considered as an interesting alternative research area.
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Affiliation(s)
- Martina Favretti
- Rheumatology Unit, Department of Internal Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Cristina Iannuccelli
- Rheumatology Unit, Department of Internal Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Manuela Di Franco
- Rheumatology Unit, Department of Internal Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
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15
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Szeliga A, Podfigurna A, Bala G, Meczekalski B. Decreased neurokinin B as a risk factor of functional hypothalamic amenorrhea. Gynecol Endocrinol 2023; 39:2216313. [PMID: 37224872 DOI: 10.1080/09513590.2023.2216313] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 04/27/2023] [Accepted: 05/15/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Neurokinin B (NKB) belongs to the tachykinin family of proteins who's regulation is essential for proper function of the reproductive system. It has been shown that patients with functional hypothalamic amenorrhea (FHA) exhibit decreased levels of serum kisspeptin. As kisspeptin secretion is regulated by NKB signaling, it is reasonable to suspect that patients with FHA will also have abnormal NKB secretion. AIM To assess NKB levels in patients with FHA and to determine whether NKB signaling is affected in these patients. We hypothesized that decreased NKB signaling is a factor contributing to the development of the FHA. MATERIALS AND METHODS A total of 147 patients with FHA and 88 healthy age-matched controls were enrolled. Baseline blood samples were drawn from both groups to measure serum concentrations of NKB, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), cortisol, dehydroepiandrosterone sulfate (DHEA-S), testosterone (T), glucose, and insulin. RESULTS Mean serum NKB levels were found to be decreased significantly in the FHA group when compared with the control group (628.35 ± 324.92 vs. 721.41 ± 337.57 ng/L, respectively p = 0.002). No statistical difference was observed in NKB-1 levels within the FHA group when selecting for normal and decreased body mass index. CONCLUSIONS Patients with FHA were found to have decreased serum NKB concentrations when compared to healthy controls. Abnormal NKB secretion is likely a key factor contributing to development of FHA.
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Affiliation(s)
- Anna Szeliga
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Agnieszka Podfigurna
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Gregory Bala
- UCD School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
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16
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Urbański A, Konopińska N, Walkowiak-Nowicka K, Roizman D, Lubawy J, Radziej M, Rolff J. Functional homology of tachykinin signalling: The influence of human substance P on the immune system of the mealworm beetle, Tenebrio molitor L. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 142:104669. [PMID: 36791872 DOI: 10.1016/j.dci.2023.104669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 02/10/2023] [Accepted: 02/12/2023] [Indexed: 06/18/2023]
Abstract
Tachykinin-related peptides (TRPs) are one of the most prominent families of neuropeptides in the animal kingdom. Insect TRPs display strong structural and functional homology to vertebrate tachykinins (TKs). To study functional homologies between these two neuropeptide families, the influence of human substance P (SP, one of the essential vertebrate TKs) on the immune system of the mealworm beetle, Tenebrio molitor L., was analysed. Human SP influences the phagocytic abilities of T. molitor haemocytes. Peptide injection leads to an increase in the number of haemocytes participating in the phagocytosis of latex beads. In contrast, incubation of haemocytes from non-injected beetles in a solution of physiological saline and SP causes a decrease in phagocytic activity. Treatment with human SP also led to increased adhesion of haemocytes, but no changes in the arrangement of the F-actin cytoskeleton were observed. Interestingly, 6 h after human SP injection, increased DNA integrity in T. molitor haemocytes was reported. The opposite effects were observed 24 h after SP injection. Human SP caused the upregulation of humoral immune responses, such as phenoloxidase (PO) activity in the T. molitor haemolymph, and the downregulation of immune-related genes encoding coleoptericin A, tenecin 3 and Toll receptor. However, genes encoding attacin 2 and cecropin were upregulated. Despite these differences, the antimicrobial activity of T. molitor haemolymph was significantly lower in beetles injected with SP than in control beetles. Moreover, an analysis of the direct influence of SP on lysozyme activity was performed. Our results suggest that SP at a concentration of 10-6 M can directly inhibit lysozyme activity. However, an opposite effect was reported after the application of SP at a concentration of 10-4 M. The presented results suggest structural and functional homology between TK signalling in vertebrates and insects. Primarily, this was visible in the context of the humoral response and general antimicrobial activity of T. molitor haemolymph. However, some of the results related to haemocyte function may also indicate the importance of the TK and TRP sequences for evoking immunological effects.
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Affiliation(s)
- A Urbański
- Department of Animal Physiology and Developmental Biology, Adam Mickiewicz University, Poznań, Uniwersytetu Poznańskiego Str. 6, 61-614, Poznań, Poland.
| | - N Konopińska
- Department of Animal Physiology and Developmental Biology, Adam Mickiewicz University, Poznań, Uniwersytetu Poznańskiego Str. 6, 61-614, Poznań, Poland
| | - K Walkowiak-Nowicka
- Department of Animal Physiology and Developmental Biology, Adam Mickiewicz University, Poznań, Uniwersytetu Poznańskiego Str. 6, 61-614, Poznań, Poland
| | - D Roizman
- Evolutionary Biology, Institute for Biology, Freie Universität Berlin, Königin-Luise-Str. 1-3, 14195, Berlin, Germany
| | - J Lubawy
- Department of Animal Physiology and Developmental Biology, Adam Mickiewicz University, Poznań, Uniwersytetu Poznańskiego Str. 6, 61-614, Poznań, Poland
| | - M Radziej
- Department of Animal Physiology and Developmental Biology, Adam Mickiewicz University, Poznań, Uniwersytetu Poznańskiego Str. 6, 61-614, Poznań, Poland
| | - J Rolff
- Evolutionary Biology, Institute for Biology, Freie Universität Berlin, Königin-Luise-Str. 1-3, 14195, Berlin, Germany; Berlin-Brandenburg Institute of Advanced Biodiversity Research (BBIB), Königin-Luise-Str. 2-4, 14195, Berlin, Germany
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17
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Martins MS, Almeida IF, Cruz MT, Sousa E. Chronic pruritus: from pathophysiology to drug design. Biochem Pharmacol 2023; 212:115568. [PMID: 37116666 DOI: 10.1016/j.bcp.2023.115568] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023]
Abstract
Pruritus, the most common symptom in dermatology, is an innate response capable of protecting skin against irritants. Nonetheless, when it lasts more than six weeks it is assumed to be a chronic pathology having a negative impact on people's lives. Chronic pruritus (CP) can occur in common and rare skin diseases, having a high prevalence in global population. The existing therapies are unable to counteract CP or are associated with adverse effects, so the development of effective treatments is a pressing issue. The pathophysiological mechanisms underlying CP are not yet completely dissected but, based on current knowledge, involve a wide range of receptors, namely neurokinin 1 receptor (NK1R), Janus kinase (JAK), and transient receptor potential (TRP) ion channels, especially transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1). This review will address the relevance of these molecular targets for the treatment of CP and molecules capable of modulating these receptors that have already been studied clinically or have the potential to possibly alleviate this pathology. According to scientific and clinical literature, there is an increase in the expression of these molecular targets in the lesioned skin of patients experiencing CP when compared with non-lesioned skin, highlighting their importance for the development of potential efficacious drugs through the design of antagonists/inhibitors.
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Affiliation(s)
- Márcia S Martins
- CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal; Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Isaobel F Almeida
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO-Applied Molecular Biosciences Unit, MedTech, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Maria T Cruz
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Emília Sousa
- CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal; Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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18
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Prashar V, Arora T, Singh R, Sharma A, Parkash J. Hypothalamic Kisspeptin Neurons: Integral Elements of the GnRH System. Reprod Sci 2023; 30:802-822. [PMID: 35799018 DOI: 10.1007/s43032-022-01027-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/23/2022] [Indexed: 12/19/2022]
Abstract
Highly sophisticated and synchronized interactions of various cells and hormonal signals are required to make organisms competent for reproduction. GnRH neurons act as a common pathway for multiple cues for the onset of puberty and attaining reproductive function. GnRH is not directly receptive to most of the signals required for the GnRH secretion during the various phases of the ovarian cycle. Kisspeptin neurons of the hypothalamus convey these signals required for the synchronized release of the GnRH. The steroid-sensitive anteroventral periventricular nucleus (AVPV) kisspeptin and arcuate nucleus (ARC) KNDy neurons convey steroid feedback during the reproductive cycle necessary for GnRH surge and pulse, respectively. AVPV region kisspeptin neurons also communicate with nNOS synthesizing neurons and suprachiasmatic nucleus (SCN) neurons to coordinate the process of the ovarian cycle. Neurokinin B (NKB) and dynorphin play roles in the GnRH pulse stimulation and inhibition, respectively. The loss of NKB and kisspeptin function results in the development of neuroendocrine disorders such as hypogonadotropic hypogonadism (HH) and infertility. Ca2+ signaling is essential for GnRH pulse generation, which is propagated through gap junctions between astrocytes-KNDy and KNDy-KNDy neurons. Impaired functioning of KNDy neurons could develop the characteristics associated with polycystic ovarian syndrome (PCOS) in rodents. Kisspeptin-increased synthesis led to excessive secretion of the LH associated with PCOS. This review provides the latest insights and understanding into the role of the KNDy and AVPV/POA kisspeptin neurons in GnRH secretion and PCOS.
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Affiliation(s)
- Vikash Prashar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Tania Arora
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Randeep Singh
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Arti Sharma
- Department of Computational Sciences, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Jyoti Parkash
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India.
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19
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Cuitavi J, Torres-Pérez JV, Lorente JD, Campos-Jurado Y, Andrés-Herrera P, Polache A, Agustín-Pavón C, Hipólito L. Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain. Neurosci Biobehav Rev 2023; 145:105011. [PMID: 36565942 DOI: 10.1016/j.neubiorev.2022.105011] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 11/29/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions. Although MORs have been related to neuroinflammation their biological mechanism remains unclear. It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of pro-inflammatory mediators and cytokines during pathological conditions. Some cytokines, including TNF-α, IL-1β and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production. In addition, Neurokinin-1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking. Therefore, inflammation in the central nervous system seems to be associated with altered/increased MORs expression, which might regulate harmful processes, such as drug addiction and pain. Here, we provide a critical evaluation on MORs' role during neuroinflammation and its implication for these conditions. Understanding MORs' functioning, their regulation and implications on drug addiction and pain may help elucidate their potential therapeutic use against these pathological conditions and associated disorders.
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Affiliation(s)
- Javier Cuitavi
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain.
| | - Jose Vicente Torres-Pérez
- Department of Cellular Biology, Functional Biology and Physical Anthropology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Jesús David Lorente
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Yolanda Campos-Jurado
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Paula Andrés-Herrera
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Ana Polache
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Carmen Agustín-Pavón
- Department of Cellular Biology, Functional Biology and Physical Anthropology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain
| | - Lucía Hipólito
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avda. Vicent Andrés Estellés s/n., 46100 Burjassot, Spain.
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20
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Suthiram J, Pieters A, Mohamed Moosa Z, Zeevaart JR, Sathekge MM, Ebenhan T, Anderson RC, Newton CL. Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi 8,Met(O 2) 11]-Substance P. Int J Mol Sci 2023; 24:2134. [PMID: 36768456 PMCID: PMC9916806 DOI: 10.3390/ijms24032134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8,Met(O2)11]-SP (DOTA-[Thi8,Met(O2)11]SP), in the theranostic pair [68Ga]Ga-/ [213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi8,Met(O2)11]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi8,Met(O2)11]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi8,Met(O2)11]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi8,Met(O2)11]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression.
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Affiliation(s)
- Janine Suthiram
- Department of Radiochemistry, The South African Nuclear Energy Corporation SOC Ltd. (Necsa), Brits 0240, South Africa
- Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
| | - Ané Pieters
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
| | - Zulfiah Mohamed Moosa
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
| | - Jan Rijn Zeevaart
- Department of Radiochemistry, The South African Nuclear Energy Corporation SOC Ltd. (Necsa), Brits 0240, South Africa
- Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Nuclear Medicine Research Infrastructure NPC, Level 5 Bridge A, Capital Park, Pretoria 0001, South Africa
| | - Mike M. Sathekge
- Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Nuclear Medicine Research Infrastructure NPC, Level 5 Bridge A, Capital Park, Pretoria 0001, South Africa
- Steve Biko Academic Hospital, Private Bag X169, Pretoria 0001, South Africa
| | - Thomas Ebenhan
- Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Nuclear Medicine Research Infrastructure NPC, Level 5 Bridge A, Capital Park, Pretoria 0001, South Africa
| | - Ross C. Anderson
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
| | - Claire L. Newton
- Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South Africa
- Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK
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21
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Blasco V, Pinto FM, Fernández-Atucha A, Dodd NP, Fernández-Sánchez M, Candenas L. Female Infertility Is Associated with an Altered Expression Profile of Different Members of the Tachykinin Family in Human Granulosa Cells. Reprod Sci 2023; 30:258-269. [PMID: 35739351 DOI: 10.1007/s43032-022-00998-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/02/2022] [Indexed: 01/11/2023]
Abstract
Neurokinin B (NKB) and its cognate receptor, NK3R, play a key role in the regulation of reproduction. NKB belongs to the family of tachykinins, which also includes substance P and neurokinin A, both encoded by the by the gene TAC1, and hemokinin-1, encoded by the TAC4 gene. In addition to NK3R, tachykinin effects are mediated by NK1R and NK2R, encoded by the genes TACR1 and TACR2, respectively. The role of these other tachykinins and receptors in the regulation of women infertility is mainly unknown. We have analyzed the expression profile of TAC1, TAC4, TACR1, and TACR2 in mural granulosa and cumulus cells from women presenting different infertility etiologies, including polycystic ovarian syndrome, advanced maternal age, low ovarian response, and endometriosis. We also studied the expression of MME, the gene encoding neprilysin, the most important enzyme involved in tachykinin degradation. Our data show that TAC1, TAC4, TACR1, TACR2, and MME expression is dysregulated in a different manner depending on the etiology of women infertility. The abnormal expression of these tachykinins and their receptors might be involved in the decreased fertility of these patients, offering a new insight regarding the diagnosis and treatment of women infertility.
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Affiliation(s)
- Víctor Blasco
- Instituto de Investigaciones Químicas, CSIC-US, Seville, Spain
- IVI-RMA Sevilla, Seville, Spain
| | | | | | - Nicolás Prados Dodd
- IVI-RMA Sevilla, Seville, Spain
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Departamento de Biología Molecular E Ingeniería Bioquímica, Universidad Pablo de Olavide, Seville, Spain
| | - Manuel Fernández-Sánchez
- IVI-RMA Sevilla, Seville, Spain.
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
- Departamento de Biología Molecular E Ingeniería Bioquímica, Universidad Pablo de Olavide, Seville, Spain.
- Departamento de Cirugía, Universidad de Sevilla, Seville, Spain.
| | - Luz Candenas
- Instituto de Investigaciones Químicas, CSIC-US, Seville, Spain
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22
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Xie Y, Xiao K, Cai T, Shi X, Zhou L, Du H, Yang J, Hu G. Neuropeptides and hormones in hypothalamus-pituitary axis of Chinese sturgeon (Acipenser sinensis). Gen Comp Endocrinol 2023; 330:114135. [PMID: 36181879 DOI: 10.1016/j.ygcen.2022.114135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/25/2022] [Accepted: 09/25/2022] [Indexed: 12/14/2022]
Abstract
The hypothalamus and pituitary serve as important neuroendocrine center, which is able to secrete a variety of neuropeptides and hormones to participate in the regulation of reproduction, growth, stress and feeding in fish. Chinese sturgeon is a basal vertebrate lineage fish with a special evolutionary status, but the information on its neuroendocrine system is relatively scarce. Using the transcriptome data on the hypothalamus-pituitary axis of Chinese sturgeon as reference, we found out 46 hypothalamus neuropeptide genes, which were involved in regulation of reproduction, growth, stress and feeding. The results of sequence alignment showed that the neuroendocrine system of Chinese sturgeon evolves slowly, which confirms that Chinese sturgeon is a species with a slow phenotypic evolution rate. In addition, we also isolated six pituitary hormones genes from Chinese sturgeon, including reproductive hormones: follicle-stimulating homone (FSH) and luteinizing hormone (LH), growth-related hormones: growth hormone (GH)/prolactin (PRL)/somatolactin (SL), and stress-related hormone gene: proopiomelanocortin (POMC). Similar to teleost, immunostaining localization analysis in Chinese sturgeon pituitary showed that LH and FSH were located in the pituitary proximal pars distalis, SL was located in the pituitary rostral pars distalis, and POMC was located in the pituitary pars intermedia and pituitary rostral pars distalis. This study will give a contribution to enrich our information on the neuroendocrine system in Chinese sturgeon.
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Affiliation(s)
- Yunyi Xie
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Kan Xiao
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei 443100, China
| | - Tianyi Cai
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Xuetao Shi
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Lingling Zhou
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China
| | - Hejun Du
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei 443100, China
| | - Jing Yang
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Yichang, Hubei 443100, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei 443100, China
| | - Guangfu Hu
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei, 430070, China.
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23
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Effects of Substance P and Neurokinin A on the Contractile Activity of Inflamed Porcine Uterus. Int J Mol Sci 2022; 23:ijms232113184. [DOI: 10.3390/ijms232113184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/17/2022] Open
Abstract
Disturbances in uterine contractile activity contribute to the development of inflammation, and recent evidence indicates that tachykinins, including substance P (SP) and neurokinin A (NKA), are involved in controlling uterine function. Here, we determined the effect of Escherichia coli (E. coli)-induced inflammation on expression of protein receptor subtypes for substance P (NK1R) and neurokinin A (NK2R) in the pig myometrium as well as their role in contractility of inflamed uterus. The severe acute endometritis developed in the E. coli group and the expression of NK1R and NK2R proteins increased in the myometrium. Compared to the pre-administration period, SP (10−6 M) reduced the amplitude and frequency in the myometrium of the E. coli group and the amplitude was higher and the frequency was lower versus other groups. NKA reduced the amplitude and increased the frequency in endometrium/myometrium of the E. coli group. In this group, the amplitude was lower and the frequency was higher than in the CON and SAL groups. Our research showed that NK2R (10−6 M) antagonist application abolished the NKA inhibitory effect on uterine amplitude. The application of the NK1R (10−5 M) antagonist together with SP revealed that the inhibitory effect of SP on uterine contractility is achieved independently of the NKR1. Additionally, taking into account the fact that NKA shows an inhibitory effect with the use of NK2R on uterine amplitude suggests the possibility of therapeutic use of the antagonist as a drug increasing uterine contractility in inflammation.
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López-Ojeda W, Hurley RA. Kisspeptin in the Limbic System: New Insights Into Its Neuromodulatory Roles. J Neuropsychiatry Clin Neurosci 2022; 34:190-195. [PMID: 35921618 DOI: 10.1176/appi.neuropsych.20220087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Wilfredo López-Ojeda
- Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center and Research and Academic Affairs Service Line, W.G. Hefner Veterans Affairs Medical Center, Salisbury, N.C. (López-Ojeda, Hurley); Departments of Psychiatry and Behavioral Medicine (López-Ojeda, Hurley) and Radiology (Hurley), Wake Forest School of Medicine, Winston-Salem, N.C.; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Hurley)
| | - Robin A Hurley
- Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center and Research and Academic Affairs Service Line, W.G. Hefner Veterans Affairs Medical Center, Salisbury, N.C. (López-Ojeda, Hurley); Departments of Psychiatry and Behavioral Medicine (López-Ojeda, Hurley) and Radiology (Hurley), Wake Forest School of Medicine, Winston-Salem, N.C.; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Hurley)
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25
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Seminara SB, Topaloglu AK. Review of human genetic and clinical studies directly relevant to GnRH signalling. J Neuroendocrinol 2022; 34:e13080. [PMID: 34970798 PMCID: PMC9299506 DOI: 10.1111/jne.13080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/28/2021] [Accepted: 12/14/2021] [Indexed: 11/30/2022]
Abstract
GnRH is the pivotal hormone in controlling the hypothalamic-pituitary gonadal (HPG) axis in humans and other mammalian species. GnRH function is influenced by a multitude of known and still unknown environmental and genetic factors. Molecular genetic studies on human families with hypogonadotropic hypogonadism over the past two decades have been instrumental in delineating the kisspeptin and neurokinin B signalling, which integrally modulates GnRH release from the hypothalamus. The identification of kisspeptin and neurokinin B ligand-receptor gene pair mutations in patients with absent puberty have paved the way to a greater understanding of the central regulation of the HPG cascade. In this article, we aim to review the literature on the genetic and clinical aspects of GnRH and its receptor, as well as the two ligand-receptor sets directly pertinent to the function of GnRH hormone signalling, kisspeptin/ kisspeptin receptor and NKB/NK3R.
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Affiliation(s)
- Stephanie B. Seminara
- Reproductive Endocrine Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - A. Kemal Topaloglu
- Division of Pediatric Endocrinology, Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi, USA
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Campo A, Dufour S, Rousseau K. Tachykinins, new players in the control of reproduction and food intake: A comparative review in mammals and teleosts. Front Endocrinol (Lausanne) 2022; 13:1056939. [PMID: 36589829 PMCID: PMC9800884 DOI: 10.3389/fendo.2022.1056939] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/07/2022] [Indexed: 12/23/2022] Open
Abstract
In vertebrates, the tachykinin system includes tachykinin genes, which encode one or two peptides each, and tachykinin receptors. The complexity of this system is reinforced by the massive conservation of gene duplicates after the whole-genome duplication events that occurred in vertebrates and furthermore in teleosts. Added to this, the expression of the tachykinin system is more widespread than first thought, being found beyond the brain and gut. The discovery of the co-expression of neurokinin B, encoded by the tachykinin 3 gene, and kisspeptin/dynorphin in neurons involved in the generation of GnRH pulse, in mammals, put a spotlight on the tachykinin system in vertebrate reproductive physiology. As food intake and reproduction are linked processes, and considering that hypothalamic hormones classically involved in the control of reproduction are reported to regulate also appetite and energy homeostasis, it is of interest to look at the potential involvement of tachykinins in these two major physiological functions. The purpose of this review is thus to provide first a general overview of the tachykinin system in mammals and teleosts, before giving a state of the art on the different levels of action of tachykinins in the control of reproduction and food intake. This work has been conducted with a comparative point of view, highlighting the major similarities and differences of tachykinin systems and actions between mammals and teleosts.
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Affiliation(s)
- Aurora Campo
- Muséum National d’Histoire Naturelle, Research Unit Unité Mixte de Recherche Biologie des Organsimes et Ecosystèmes Aquatiques (UMR BOREA), Biology of Aquatic Organisms and Ecosystems, Centre National pour la Recherche Scientifique (CNRS), Institut de Recherche pour le Développemen (IRD), Sorbonne Université, Paris, France
- Volcani Institute, Agricultural Research Organization, Rishon LeTsion, Israel
| | - Sylvie Dufour
- Muséum National d’Histoire Naturelle, Research Unit Unité Mixte de Recherche Biologie des Organsimes et Ecosystèmes Aquatiques (UMR BOREA), Biology of Aquatic Organisms and Ecosystems, Centre National pour la Recherche Scientifique (CNRS), Institut de Recherche pour le Développemen (IRD), Sorbonne Université, Paris, France
| | - Karine Rousseau
- Muséum National d’Histoire Naturelle, Research Unit Unité Mixte de Recherche Biologie des Organsimes et Ecosystèmes Aquatiques (UMR BOREA), Biology of Aquatic Organisms and Ecosystems, Centre National pour la Recherche Scientifique (CNRS), Institut de Recherche pour le Développemen (IRD), Sorbonne Université, Paris, France
- Muséum National d’Histoire Naturelle, Research Unit PhyMA Physiologie Moléculaire et Adaptation CNRS, Paris, France
- *Correspondence: Karine Rousseau,
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27
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Sanders KM, Baker SA, Drumm BT, Kurahashi M. Ca 2+ Signaling Is the Basis for Pacemaker Activity and Neurotransduction in Interstitial Cells of the GI Tract. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:229-241. [PMID: 36587162 DOI: 10.1007/978-3-031-05843-1_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Years ago gastrointestinal motility was thought to be due to interactions between enteric nerves and smooth muscle cells (SMCs) in the tunica muscularis. Thus, regulatory mechanisms controlling motility were either myogenic or neurogenic. Now we know that populations of interstitial cells, c-Kit+ (interstitial cells of Cajal or ICC), and PDGFRα+ cells (formerly "fibroblast-like" cells) are electrically coupled to SMCs, forming the SIP syncytium. Pacemaker and neurotransduction functions are provided by interstitial cells through Ca2+ release from the endoplasmic reticulum (ER) and activation of Ca2+-activated ion channels in the plasma membrane (PM). ICC express Ca2+-activated Cl- channels encoded by Ano1. When activated, Ano1 channels produce inward current and, therefore, depolarizing or excitatory effects in the SIP syncytium. PDGFRα+ cells express Ca2+-activated K+ channels encoded by Kcnn3. These channels generate outward current when activated and hyperpolarizing or membrane-stabilizing effects in the SIP syncytium. Inputs from enteric and sympathetic neurons regulate Ca2+ transients in ICC and PDGFRα+ cells, and currents activated in these cells conduct to SMCs and regulate contractile behaviors. ICC also serve as pacemakers, generating slow waves that are the electrophysiological basis for gastric peristalsis and intestinal segmentation. Pacemaker types of ICC express voltage-dependent Ca2+ conductances that organize Ca2+ transients, and therefore Ano1 channel openings, into clusters that define the amplitude and duration of slow waves. Ca2+ handling mechanisms are at the heart of interstitial cell function, yet little is known about what happens to Ca2+ dynamics in these cells in GI motility disorders.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA.
| | - Salah A Baker
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA
| | - Bernard T Drumm
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA
| | - Masaaki Kurahashi
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Iowa, Iowa City, USA
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Zuo C, Lyu L, Zou W, Wen H, Li Y, Qi X. TAC3/TACR3 System Function in the Catadromous Migration Teleost, Anguilla japonica. Front Endocrinol (Lausanne) 2022; 13:848808. [PMID: 35937808 PMCID: PMC9355281 DOI: 10.3389/fendo.2022.848808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Neurokinin B (NKB), a member of the tachykinin (TAC) family, plays important roles in mammalian neuropeptide secretion in related to reproduction. However, its potential role in spawning migration teleost is less clear. In the present study, Japanese eel (Anguilla japonica) was employed to study the performance of NKB in regulating reproduction. Results showed that two tac3 and one tacr3 genes were identified in Japanese eel. Sequence analysis showed that two tac3 transcripts, tac3a and tac3b, encode four NKBs: NKBa-13, NKBa-10, NKBb-13, and NKBb-10. However, compared with other species, a mutation caused early termination of TACR3 protein was confirmed, leading to the loss of the 35 amino acid (aa) C-terminal of the receptor. Expression analysis in different tissues showed that both tac3a and tac3b mRNAs were highly expressed in the brain. In situ hybridization localized both tac3a and tac3b mRNAs to several brain regions, mainly in the telencephalon and hypothalamus. Because of the mutation in TACR3 of Japanese eel, we further analyzed whether it could activate the downstream signaling pathway. Luciferase assay results showed the negative regulation of cAMP Response Element (CRE) and Sterol Response Element (SRE) signal pathways by Japanese eel NKBs. Intraperitoneal injection of four different NKB mature peptides at 100 ng/g had negative effect on either gnrh or gth gene expression. However, the high concentration of NKBa-10 and NKBb-13 (1,000 ng/g) upregulated mgnrh and fshb or lhb expression level significantly, which may be mediated by other receptors. In general, the NKBs/NK3Rs system has important functions in regulating eel puberty onset.
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Affiliation(s)
- Chenpeng Zuo
- Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China
| | - Likang Lyu
- Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China
| | - Wenhui Zou
- College of Ocean, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou, China
| | - Haishen Wen
- Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China
| | - Yun Li
- Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China
| | - Xin Qi
- Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China
- *Correspondence: Xin Qi,
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Lee S, Kim MA, Park JM, Park K, Sohn YC. Multiple tachykinins and their receptors characterized in the gastropod mollusk Pacific abalone: Expression, signaling cascades, and potential role in regulating lipid metabolism. Front Endocrinol (Lausanne) 2022; 13:994863. [PMID: 36187101 PMCID: PMC9521575 DOI: 10.3389/fendo.2022.994863] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Tachykinin (TK) families, including the first neuropeptide substance P, have been intensively explored in bilaterians. Knowledge of signaling of TK receptors (TKRs) has enabled the comprehension of diverse physiological processes. However, TK signaling systems are largely unknown in Lophotrochozoa. This study identified two TK precursors and two TKR isoforms in the Pacific abalone Haliotis discus hannai (Hdh), and characterized Hdh-TK signaling. Hdh-TK peptides harbored protostomian TK-specific FXGXRamide or unique YXGXRamide motifs at the C-termini. A phylogenetic analysis showed that lophotrochozoan TKRs, including Hdh-TKRs, form a monophyletic group distinct from arthropod TKRs and natalisin receptor groups. Although reporter assays demonstrated that all examined Hdh-TK peptides activate intracellular cAMP accumulation and Ca2+ mobilization in Hdh-TKR-expressing mammalian cells, Hdh-TK peptides with N-terminal aromatic residues and C-terminal FXGXRamide motifs were more active than shorter or less aromatic Hdh-TK peptides with a C-terminal YXGXRamide. In addition, we showed that ligand-stimulated Hdh-TKRs mediate ERK1/2 phosphorylation in HEK293 cells and that ERK1/2 phosphorylation is inhibited by PKA and PKC inhibitors. In three-dimensional in silico Hdh-TKR binding modeling, higher docking scores of Hdh-TK peptides were consistent with the lower EC50 values in the reporter assays. The transcripts for Hdh-TK precursors and Hdh-TKR were highly expressed in the neural ganglia, with lower expression levels in peripheral tissues. When abalone were starved for 3 weeks, Hdh-TK1 transcript levels, but not Hdh-TK2, were increased in the cerebral ganglia (CG), intestine, and hepatopancreas, contrasting with the decreased lipid content and transcript levels of sterol regulatory element-binding protein (SREBP). At 24 h post-injection in vivo, the lower dose of Hdh-TK1 mixture increased SREBP transcript levels in the CG and hepatopancreas and accumulative food consumption of abalone. Higher doses of Hdh-TK1 and Hdh-TK2 mixtures decreased the SREBP levels in the CG. When Hdh-TK2-specific siRNA was injected into abalone, intestinal SREBP levels were significantly increased, whereas administration of both Hdh-TK1 and Hdh-TK2 siRNA led to decreased SREBP expression in the CG. Collectively, our results demonstrate the first TK signaling system in gastropod mollusks and suggest a possible role for TK peptides in regulating lipid metabolism in the neural and peripheral tissues of abalone.
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Affiliation(s)
- Seungheon Lee
- Department of Marine Bioscience, Gangneung-Wonju National University, Gangneung, South Korea
| | - Mi Ae Kim
- Department of Marine Bioscience, Gangneung-Wonju National University, Gangneung, South Korea
- East Coast Life Sciences Institute, Gangneung-Wonju National University, Gangneung, South Korea
| | - Jong-Moon Park
- College of Pharmacy, Gachon University, Incheon, South Korea
| | - Keunwan Park
- Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung, South Korea
| | - Young Chang Sohn
- Department of Marine Bioscience, Gangneung-Wonju National University, Gangneung, South Korea
- *Correspondence: Young Chang Sohn,
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Shi X, Ye C, Qin X, Zhou L, Xia C, Cai T, Xie Y, Yin Z, Hu G. Novel Pituitary Actions of TAC4 Gene Products in Teleost. Int J Mol Sci 2021; 22:ijms222312893. [PMID: 34884698 PMCID: PMC8657723 DOI: 10.3390/ijms222312893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Tachykinin 4 (TAC4) is the latest member of the tachykinin family involved in several physiological functions in mammals. However, little information is available about TAC4 in teleost. In the present study, we firstly isolated TAC4 and six neurokinin receptors (NKRs) from grass carp brain and pituitary. Sequence analysis showed that grass carp TAC4 could encode two mature peptides (namely hemokinin 1 (HK1) and hemokinin 2 (HK2)), in which HK2 retained the typical FXGLM motif in C-terminal of tachyinin, while HK1 contained a mutant VFGLM motif. The ligand-receptor selectivity showed that HK2 could activate all 6 NKRs but with the highest activity for the neurokinin receptor 2 (NK2R). Interestingly, HK1 displayed a very weak activation for each NKR isoform. In grass carp pituitary cells, HK2 could induce prolactin (PRL), somatolactin α (SLα), urotensin 1 (UTS1), neuromedin-B 1 (NMB1), cocaine- and amphetamine-regulated transcript 2 (CART2) mRNA expression mediated by NK2R and neurokinin receptor 3 (NK3R) via activation cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3)/protein kinase C (PKC) and calcium2+ (Ca2+)/calmodulin (CaM)/calmodulin kinase-II (CaMK II) cascades. However, the corresponding stimulatory effects triggered by HK1 were found to be notably weaker. Furthermore, based on the structural base for HK1, our data suggested that a phenylalanine (F) to valine (V) substitution in the signature motif of HK1 might have contributed to its weak agonistic actions on NKRs and pituitary genes regulation.
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Affiliation(s)
- Xuetao Shi
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Cheng Ye
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Xiangfeng Qin
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Lingling Zhou
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Chuanhui Xia
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Tianyi Cai
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Yunyi Xie
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
| | - Zhan Yin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Correspondence: (Z.Y.); (G.H.)
| | - Guangfu Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (X.S.); (C.Y.); (X.Q.); (L.Z.); (C.X.); (T.C.); (Y.X.)
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Correspondence: (Z.Y.); (G.H.)
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Xu S, Zhou L, Guo S, Hu Q, Shi X, Xia C, Zhang H, Ye C, Jia Y, Hu G. Different pituitary action of NK3Ra and NK3Rb in grass carp. Gen Comp Endocrinol 2021; 313:113829. [PMID: 34087185 DOI: 10.1016/j.ygcen.2021.113829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/03/2021] [Accepted: 05/31/2021] [Indexed: 10/21/2022]
Abstract
In mammals, NK3R is the specific receptor for NKB, which played an important role in reproduction. Recently, two NK3R isoforms, namely NK3Ra and NK3Rb, have been identified in fish. However, little is known about the pituitary actions of the two NK3R isoforms in fish. In this study, both NK3Ra and NK3Rb were isolated from grass carp pituitary. Although their sequence similarity was only 61.6%, the two NK3R isoforms displayed similar ligand selectivity and binding affinity to TAC3 gene products (NKBa, NKBRPa and NKBRPb). In addition, both NK3Ra and NK3Rb displayed similar signaling pathways, including PKA, PKC, MAPK and Ca2+ cascades. Tissue distribution indicated that both NK3Ra and NK3Rb were highly detected in grass carp pituitary. Further study found that NK3Ra was mainly located in pituitary LHβ cells, while NK3Rb was only detected in pituitary SLα cells. Furthermore, NK3Ra and NK3Rb activation could induce LHβ and SLα promoter activity, respectively. These results suggested that the two NK3R isoforms displayed different pituitary actions in fish. Using grass carp pituitary cells as model, we found that PACAP could significantly reduce NK3Ra, but induce NK3Rb mRNA expression coupled with cAMP/PKA and PLC/PKC pathways. Interestingly, PACAP could also significantly inhibit LHβ, but stimulate SLα mRNA expression in grass carp pituitary cells. Furthermore, NK3R antagonist could not only inhibit LHβ mRNA expression, but also block PACAP-induced SLα mRNA expression in grass carp pituitary cells. These results suggested that NK3Ra and NK3Rb could mediate PACAP-reduced LHβ and -induced SLα mRNA expression in grass carp pituitary, respectively.
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Affiliation(s)
- Shaohua Xu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Lingling Zhou
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Shuming Guo
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Qiongyao Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Xuetao Shi
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Chuanhui Xia
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Huiying Zhang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Cheng Ye
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Yongyi Jia
- Agriculture Ministry Key Laboratory of Healthy Freshwater Aquaculture, Key Laboratory of Fish Health and Nutrition of Zhejiang Province, Zhejiang Institute of Freshwater Fisheries, Huzhou 313001, China.
| | - Guangfu Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
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Al Abed AS, Reynolds NJ, Dehorter N. A Second Wave for the Neurokinin Tac2 Pathway in Brain Research. Biol Psychiatry 2021; 90:156-164. [PMID: 33867115 DOI: 10.1016/j.biopsych.2021.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022]
Abstract
Despite promising advances in basic research of the neurokinin B/Tac2 pathway in both animals and humans, clinical applications are yet to be implemented. This is likely because of our limited understanding of the action of the pathway in the brain. While this system controls neuronal activity in multiple regions, the precise impact of Tac2-induced cellular responses on behavior remains unclear. Recently, elegant studies revealed a key contribution to stress-related behaviors and memory. Here, we discuss the crucial importance of bridging the gap between the Tac2 pathway's involvement in cell physiology and cognition to comprehend its role in health and disease. We propose that a better understanding of the Tac2 pathway in the brain could provide an essential perspective for basic investigations, which in turn will feed clinical research.
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Affiliation(s)
- A Shaam Al Abed
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Nathan J Reynolds
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Nathalie Dehorter
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
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Satarker S, Maity S, Mudgal J, Nampoothiri M. In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer's disease. Mol Divers 2021; 26:443-466. [PMID: 34331670 PMCID: PMC8885547 DOI: 10.1007/s11030-021-10276-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023]
Abstract
Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer’s disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl l Tryptophan (l-NAT) on NK1R, this is the first in silico screening of l-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The l-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The l-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of l-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein–ligand interactions with an acceptable root mean square deviation. The protein–ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein–ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of l-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.
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Affiliation(s)
- Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Swastika Maity
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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The Effect of SP/NK1R on the Expression and Activity of Catalase and Superoxide Dismutase in Glioblastoma Cancer Cells. Biochem Res Int 2021; 2021:6620708. [PMID: 33976938 PMCID: PMC8084669 DOI: 10.1155/2021/6620708] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 01/29/2023] Open
Abstract
Introduction Glioblastoma is the most malignant brain tumor with different therapeutic protocols, including surgery, radiotherapy, and chemotherapy. Substance P (SP), a peptide released by sensory nerves, increases cellular excitability by activating the neurokinin-1 receptor (NK1R) in several human tumor cells. Aprepitant is a potent and long-lasting NK1R antagonist, considered a new agent for inhibiting proliferation and induction of apoptosis in malignant cells. This study aimed to evaluate the effects of the SP/NK1R system on the expression and activity of catalase and superoxide dismutase (SOD) in the glioblastoma U87 cancer cell line. Methods Cytotoxicity was measured by the resazurin test, 24 hours after treatment, with increasing aprepitant concentrations. The production of reactive oxygen species (ROS) was also measured 24 hours after treatment with SP and aprepitant. Enzymes activity of catalase and SOD was measured using the corresponding assay kits. Real-time PCR also measured their expression. Results Aprepitant significantly reduced the viability of U87 cells in a concentration-dependent manner. ROS production was significantly reduced, and the activity of catalase and SOD increased after treatment with aprepitant. The expression of catalase and SOD enzymes also increased significantly in the presence of aprepitant. Conclusion The present study showed that aprepitant inhibited SP's oxidizing effects via inducing the antioxidant effects of catalase and SOD in the U87 cell line. Therefore, this drug might be introduced as a potential candidate for controlling glioblastoma cancer in animal models and clinical trials.
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Kant V, Mahapatra PS, Gupta V, Bag S, Gopalakrishnan A, Kumar D, Kumar D. Substance P, a Neuropeptide, Promotes Wound Healing via Neurokinin-1 Receptor. INT J LOW EXTR WOUND 2021; 22:291-297. [PMID: 33856252 DOI: 10.1177/15347346211004060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Substance P (SP), an endogenous neuropeptide, mediates intracellular signaling, mainly through a tachykinin receptor. The tachykinin receptors family consists of neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 receptors. Our previous studies on SP have shown its wound healing potentials. But the exact mechanism of wound healing by SP is not exactly known. In view of this, the present study was aimed at evaluating the in vitro wound healing effect of SP alone and in the presence of NK-1, NK-2, and both receptor antagonists. Scratch assay, transwell assay, and tumor growth factor-beta 1 (TGF-β1) assay were performed on buffalo fetal fibroblast culture. The cotreatment of fibroblast cultures with SP alone during the 24 h caused the significant proliferation and migrations of cells in both horizontal and vertical directions. The SP in the presence of spantide II (NK-1 antagonist) failed to stimulate this migration. The treatment of cells with SP in the presence of NK-2 antagonist treatment also showed a significant reduction of migration of cells with respect to SP treatment alone. The SP in the presence of both NK-1 and NK-2 antagonists failed to stimulate the horizontal migration of cells and most of the ineffectiveness of SP was observed in this combination. The TGF-β1 levels were significantly higher in the supernatants of cells that were exposed to SP alone. All other treatments have significantly lower TGF-β1 levels than SP alone treatment. It is concluded that different actions on fibroblast cells by SP were mainly mediated through the NK-1 receptor.
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Affiliation(s)
- Vinay Kant
- Division of Pharmacology and Toxicology, 30072Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P., India.,Department of Veterinary Pharmacology & Toxicology, COVS, LUVAS, Hisar, Haryana, India
| | - Puspendra S Mahapatra
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar, U.P., India
| | - Vijayta Gupta
- Department of Chemistry, 29074University of Jammu, Jammu & Kashmir, India
| | - Sadhan Bag
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar, U.P., India
| | - Anu Gopalakrishnan
- Division of Pharmacology and Toxicology, 30072Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P., India
| | - Dhirendra Kumar
- Division of Pharmacology and Toxicology, 30072Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P., India
| | - Dinesh Kumar
- Division of Pharmacology and Toxicology, 30072Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P., India
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Ben-Shushan S, Miller Y. Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases. J Phys Chem B 2021; 125:2796-2811. [PMID: 33570949 PMCID: PMC8389909 DOI: 10.1021/acs.jpcb.0c11151] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by deposits of amyloid proteins. The homeostasis of metal ions is crucial for the normal biological functions in the brain. However, in AD and PD, the imbalance of metal ions leads to formation of amyloid deposits. In the past four decades, there has been extensive effort to design compound agents than can chelate metal ions with the aim of preventing the formation of the amyloid deposits. Unfortunately, the compounds to date that were designed were not successful candidates to be used in clinical trials. Neuropeptides are small molecules that are produced and released by neurons. It has been shown that neuropeptides have neuroprotective effects in the brain and reduce the formation of amyloid deposits. This Review Article is focused on the function of neuropeptides as metal chelators. Experimental and computational studies demonstrated that neuropeptides could bind metal ions, such as Cu2+ and Zn2+. This Review Article provides perspectives and initiates future studies to investigate the role of neuropeptides as metal chelators in neurodegenerative diseases.
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Affiliation(s)
- Shira Ben-Shushan
- Department of Chemistry, Ben-Gurion University of the Negev, P.O. Box 653, Be'er Sheva 84105, Israel.,Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel
| | - Yifat Miller
- Department of Chemistry, Ben-Gurion University of the Negev, P.O. Box 653, Be'er Sheva 84105, Israel.,Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel
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Abstract
The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, neurokinin B(NKB). The role of Tacr3/NK3R in growth and reproduction has been extensively studied, but Tacr3/NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system, including mood disorders, chronic pain, learning and memory deficiencies, Alzheimer's disease, Parkinson's disease, addiction-related processes, hypoxic-ischemic encephalopathy, body fluid management, neural development, and schizophrenia. Here, we summarize the structure of NK3R/NKB and its cellular signaling as well as the expression of Tacr3/NK3R in the nervous system, and we provide a comprehensive summary of the role of Tacr3/NK3R in neurological diseases, including reproduction-related disorders and other neurological diseases. At the end of this review, we propose the hypothesis that Tacr3/NK3R mediates a variety of brain functions by affecting the excitability of different neurons with specific functions. On the basis of this "excited or not" hypothesis, more studies related to Tacr3 should be carried out in other nervous system diseases in order to better understand the biological roles of Tacr3.
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Affiliation(s)
- Wen-wen Zhang
- Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Yanqing Wang
- Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Yu-Xia Chu
- Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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38
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Experimental Hypomagnesemia Induces Neurogenic Inflammation and Cardiac Dysfunction. HEARTS 2020. [DOI: 10.3390/hearts1020011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, cardiovascular, renal and other systems. In Mg-deficient rodents, early elevations in circulating levels of the neuropeptide, substance P (SP) may trigger subsequent deleterious inflammatory/oxidative/nitrosative stress events. Evidence also suggests that activity of neutral endopeptidase (NEP, neprilysin), the major SP-degrading enzyme, may be impaired during later stages of Mg deficiency, and this may sustain the neurogenic inflammatory response. In this article, experimental findings using substance P receptor blockade, NEP inhibition, and N-methyl-D-aspartate (NMDA) receptor blockade demonstrated the connection between hypomagnesemia, neurogenic inflammation, oxidative stress and enhanced cardiac dysfunction. Proof of concept concerning neurogenic inflammation is provided using an isolated perfused rat heart model exposed to acute reductions in perfusate magnesium concentrations.
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Dorokhov VS, Nelyubina YV, Ioffe SL, Sukhorukov AY. Asymmetric Synthesis of Merck's Potent hNK 1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides. J Org Chem 2020; 85:11060-11071. [PMID: 32786617 DOI: 10.1021/acs.joc.0c01322] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
An asymmetric total synthesis of Merck's hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C-H oxygenation using a novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine subunit was constructed with exceptionally high regio- and stereoselectivities. The approach described here can be used to access enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant molecules and organocatalysts.
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Affiliation(s)
- Valentin S Dorokhov
- N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect, 47, Moscow 119991, Russia
| | - Yulia V Nelyubina
- A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov str. 28, Moscow 119991, Russia
| | - Sema L Ioffe
- N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect, 47, Moscow 119991, Russia
| | - Alexey Yu Sukhorukov
- N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect, 47, Moscow 119991, Russia.,Plekhanov Russian University of Economics, Stremyanny per. 36, Moscow 117997, Russia
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40
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Blasco V, Pinto FM, Fernández-Atucha A, González-Ravina C, Fernández-Sánchez M, Candenas L. Female infertility is associated with an altered expression of the neurokinin B/neurokinin B receptor and kisspeptin/kisspeptin receptor systems in ovarian granulosa and cumulus cells. Fertil Steril 2020; 114:869-878. [PMID: 32811673 DOI: 10.1016/j.fertnstert.2020.05.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/17/2020] [Accepted: 05/05/2020] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To analyze and compare the expression profile of TAC3, TACR3, KISS1, and KISS1R in mural granulosa and cumulus cells from healthy oocyte donors and patients with different infertility etiologies, including advanced maternal age, endometriosis, and low ovarian response. DESIGN Genetic association study. SETTING Private fertility clinic and public research laboratory. PATIENT(S) Healthy oocyte donors and infertile women undergoing in vitro fertilization (IVF) treatment. INTERVENTION(S) IVF. MAIN OUTCOME MEASURE(S) Gene expression levels of KISS1, KISS1R, TAC3, and TACR3 in human mural granulosa and cumulus cells. RESULT(S) Infertile women showed statistically significantly altered expression levels of KISS1 (-2.57 ± 2.30 vs. -1.37 ± 2.11), TAC3 (-1.21 ± 1.40 vs. -1.49 ± 1.98), and TACR3 (-0.77 ± 1.36 vs. -0.03 ± 0.56) when compared with healthy oocyte donors. Advanced maternal age patients, endometriosis patients, and low responders showed specific and altered expression profiles in comparison with oocyte donors. CONCLUSION(S) Abnormal expression levels of KISS1/KISS1R and TAC3/TACR3 systems in granulosa cells might be involved in the decreased fertility associated to advanced maternal age, endometriosis, and low ovarian response.
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Affiliation(s)
- Victor Blasco
- Instituto de Investigaciones Químicas, CSIC, Seville, Spain; IVI-RMA Seville, Seville, Spain
| | | | | | | | - Manuel Fernández-Sánchez
- IVI-RMA Seville, Seville, Spain; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Departamento de Cirugía, Universidad de Sevilla, Seville, Spain; Departamento de Biología Molecular e Ingeniería Bioquímica, Universidad Pablo de Olavide, Seville, Spain.
| | - Luz Candenas
- Instituto de Investigaciones Químicas, CSIC, Seville, Spain
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41
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Jain AR, Britton ZT, Markwalter CE, Robinson AS. Improved ligand-binding- and signaling-competent human NK2R yields in yeast using a chimera with the rat NK2R C-terminus enable NK2R-G protein signaling platform. Protein Eng Des Sel 2020; 32:459-469. [PMID: 32400863 DOI: 10.1093/protein/gzaa009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 03/09/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023] Open
Abstract
The tachykinin 2 receptor (NK2R) plays critical roles in gastrointestinal, respiratory and mental disorders and is a well-recognized target for therapeutic intervention. To date, therapeutics targeting NK2R have failed to meet regulatory agency approval due in large part to the limited characterization of the receptor-ligand interaction and downstream signaling. Herein, we report a protein engineering strategy to improve ligand-binding- and signaling-competent human NK2R that enables a yeast-based NK2R signaling platform by creating chimeras utilizing sequences from rat NK2R. We demonstrate that NK2R chimeras incorporating the rat NK2R C-terminus exhibited improved ligand-binding yields and downstream signaling in engineered yeast strains and mammalian cells, where observed yields were better than 4-fold over wild type. This work builds on our previous studies that suggest exchanging the C-termini of related and well-expressed family members may be a general protein engineering strategy to overcome limitations to ligand-binding and signaling-competent G protein-coupled receptor yields in yeast. We expect these efforts to result in NK2R drug candidates with better characterized signaling properties.
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Affiliation(s)
- Abhinav R Jain
- Department of Chemical and Biomolecular Engineering, Tulane University, 6823 St Charles Ave, New Orleans, LA, 70118, USA
| | - Zachary T Britton
- Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St, Newark, DE, 19716, USA.,AstraZeneca, Antibody Discovery and Protein Engineering, Gaithersburg, MD 20878, USA
| | - Chester E Markwalter
- Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St, Newark, DE, 19716, USA.,Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
| | - Anne S Robinson
- Department of Chemical and Biomolecular Engineering, Tulane University, 6823 St Charles Ave, New Orleans, LA, 70118, USA.,Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St, Newark, DE, 19716, USA.,Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Williams KA, Huang AH, Belzberg M, Kwatra SG. Prurigo nodularis: Pathogenesis and management. J Am Acad Dermatol 2020; 83:1567-1575. [PMID: 32461078 DOI: 10.1016/j.jaad.2020.04.182] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/12/2022]
Abstract
Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.
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Affiliation(s)
- Kyle A Williams
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Amy H Huang
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
| | - Micah Belzberg
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
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Lorente L, Martín MM, González-Rivero AF, Pérez-Cejas A, Sabatel R, Ramos-Gómez L, Argueso M, Cáceres JJ, Solé-Violán J, Jiménez A, García-Marín V. Serum substance P levels and early mortality of spontaneous intracerebral haemorrhage patients. J Stroke Cerebrovasc Dis 2020; 29:104893. [PMID: 32414584 DOI: 10.1016/j.jstrokecerebrovasdis.2020.104893] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/10/2020] [Accepted: 04/13/2020] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION AND GOAL Substance P, a neuropeptide of the tachykinin family, is involved in the neuroinflammation of different diseases of the central nervous system. To our knowledge, there is no published data on the level of circulating substance P levels in the prognosis of patients with spontaneous intracerebral hemorrhage (ICH). Therefore, the objectives of this observational and prospective study were to determine whether serum substance P levels in ICH patients were associated with early mortality and whether could be used in the mortality prognostic. MATERIAL AND METHODS We included patients with severe primary supratentorial ICH (defined as Glasgow Coma Scale < 9) from 6 Intensive Care Units of Spanish hospitals. We determined serum substance P levels at the time of severe ICH diagnosis, at fourth and at eighth day. Thirty-day mortality was considered the end-point study. FINDINGS Non-surviving (n=53) compared to surviving ICH patients (n=64) showed higher serum substance P levels at day 1 (p<0.001), day 4 (p<0.001) and day 8 (p<0.001). The area under the curve for 30-day mortality prediction by serum substance P levels was of 79% (95% CI = 70-86%; p<0.001). Kaplan-Meier analysis showed a higher 30-day mortality in patients with serum substance P levels>503 pg/mL (Hazard ratio=14.7; 95% CI=6.88-31.55; p<0.001). Multiple logistic regression analysis showed an association between serum substance P levels and 30-day mortality (Odds Ratio=1.006; 95% CI=1.002-1.010; p=0.004) controlling for ICH score, midline shift, glycemia, early evacuation of ICH. CONCLUSIONS Thus, the novel aspects our study include that serum substance P levels in severe primary ICH patients were higher in non-surviving than in surviving patients, that serum substance P levels were associated with early mortality controlling for other variables, and that serum substance P levels could be used as biomarkers of prognosis.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, Santa Cruz de Tenerife 38010, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Tenerife, Spain
| | - Rafael Sabatel
- Department of Radiology, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
| | - Luis Ramos-Gómez
- Intensive Care Unit, Hospital General La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma 38713, Spain
| | - Mónica Argueso
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez n°17-19, Valencia 46004, Spain
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain.
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain.
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
| | - Victor García-Marín
- Department of Neurosurgery, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
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Ebrahimi S, Javid H, Alaei A, Hashemy SI. New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with microRNAs. Clin Genet 2020; 98:322-330. [PMID: 32266968 DOI: 10.1111/cge.13750] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/17/2020] [Accepted: 04/02/2020] [Indexed: 12/24/2022]
Abstract
The neuropeptide substance P (SP) triggers a variety of tumor-promoting signaling pathways through the activation of neurokinin-1receptor (NK1R), a class of neurokinin G protein-coupled receptors superfamily. Recent researches in our and other laboratories have shown the overexpression of both SP and NK1R in breast cancer (BC) patients. SP/NK1R signaling is strongly implicated in the pathogenesis of BC through affecting cell proliferation, migration, metastasis, angiogenesis, and resistance. Therefore, SP/NK1R signaling responses must be rigorously regulated; otherwise, they would contribute to a more aggressive BC phenotype. Recently, microRNAs (miRNAs) as a specific class of epigenetic regulators have been shown to regulate NK1R and thus, controlling SP/NK1R signaling responses in BC. This review summarizes the current knowledge of the role of SP/NK1R signaling and its therapeutic potentials in BC. We also provide an overview regarding the effects of miRNA-mediated NK1R regulatory mechanisms in controlling BC tumorigenesis to gain a clearer view and thus better management of cancer.
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Affiliation(s)
- Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hosein Javid
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Alaei
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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45
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Lorestani S, Ghahremanloo A, Jangjoo A, Abedi M, Hashemy SI. Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in colorectal cancer. Mol Biol Rep 2020; 47:3469-3474. [PMID: 32277443 DOI: 10.1007/s11033-020-05432-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/03/2020] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC) is known as the most common form of malignancies in the world and its occurrence is annually increasing. Due to the relatively high death rates in patients, finding better diagnostic and prognostic factors are required. Substance P (SP) belongs to the tachykinin family that acts as an immunomodulator by binding to the neurokinin-1 receptor (NK1R). The interaction of SP with NK1R might be involved in tumor cell proliferation, angiogenesis, and migration. Hence, this study was aimed to evaluate the serum SP level and tissue distribution of NK1Rs in CRC. Also, we assessed the relationship between tissue distribution of NK1R and some different tumor characteristics, including tumor size, and lymph node status. Recruiting 38 patients primarily diagnosed with CRC, the tissue distribution of NK1R was immunohistochemically evaluated in tumor tissues and their adjacent normal tissue. The serum level of SP was measured using an ELISA method in both cases and healthy control group. The SP value was significantly increased in the serum of patients in comparison with the healthy group (p = 0.001). Tumor tissues expressed a higher number of NK1R than adjacent normal tissues (p = 0.01) considering both the percentage of stained cells and intensity of staining. However, there was not any statistically significant relevance between NK1R distribution and tumor characteristics. The SP/NK1R system is involved in tumorigenesis of CRC, and might be suggested as a potent prognostic or diagnostic factor, or a new target in the treatment of CRC.
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Affiliation(s)
- Shima Lorestani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atefeh Ghahremanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Jangjoo
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maedeh Abedi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Czelejewska W, Zmijewska A, Dziekonski M, Okrasa S. The role of neurokinin A and its receptor in the regulation of prolactin secretion by the anterior pituitary of cyclic pigs. Reprod Domest Anim 2020; 55:604-612. [PMID: 32086962 DOI: 10.1111/rda.13659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 02/15/2020] [Indexed: 11/30/2022]
Abstract
In pigs, plasma prolactin concentration markedly changes during the oestrous cycle and the regulation of its secretion is very complex. The contribution of neurokinins in this process has not been sufficiently delineated. The aim of the study was to examine the effects of neurokinin A (NKA) on prolactin synthesis and secretion in cyclic gilts. The expression of NKA precursor (Ppta) and receptor (Tacr2) genes as well as NKA and TACR proteins content in the porcine pituitaries (days 2-3, 9-10, 12-13, 15-16 and 19-20 of the cycle) was determined. Furthermore, the in vitro influence of NKA on the expression of prolactin (Prl), dopamine receptor (D2r), TRH receptor (Trhr) genes and prolactin secretion by the porcine pituitary cells (days 9-10, 15-16 and 19-20 of the cycle) was assessed. The expression of Ppta and Tacr2 as well as NKA and TACR proteins in the pituitary tissue has been changing throughout the oestrous cycle. NKA affected in vitro the expression of studied genes and prolactin secretion depending on the stage of the cycle, dose of NKA and/or duration of the cell incubation. Altogether, the study indicates that NKA is engaged in the modulation of prolactin secretion in the pig during the oestrous cycle.
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Affiliation(s)
- Wioleta Czelejewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Agata Zmijewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Mariusz Dziekonski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Stanislaw Okrasa
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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Lorente L, Martín MM, Pérez-Cejas A, González-Rivero AF, Argueso M, Ramos L, Solé-Violán J, Cáceres JJ, Jiménez A, García-Marín V. High serum substance P levels and mortality after malignant middle cerebral artery infarction. J Crit Care 2020; 57:1-4. [PMID: 31991332 DOI: 10.1016/j.jcrc.2020.01.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 01/13/2020] [Accepted: 01/19/2020] [Indexed: 10/25/2022]
Abstract
PURPOSE Previously our team found higher serum substance P concentrations at day 1 of a malignant middle cerebral artery infarction (MMCAI) in non-surviving than in surviving patients. Thus, the objective of this study was to determine whether serum substance P levels during the first week of MMCAI could predict mortality. METHODS We included patients with MMCAI defined as computed tomography findings of acute infarction in at least of 50% of the territory and Glasgow Coma Scale ≤8. We determined serum concentrations of substance P on days 1, 4 and 8 of MMCAI. Thirty-day mortality was the study end-point. RESULTS Serum substance P concentrations at days 1 (p < .001), 4 (p < .001), and 8 (p = .001) of MMCAI in non-surviving (n = 34) were higher than in surviving patients (n = 34). Receiver operating characteristic analyses showed that serum substance P concentrations at days 1, 4, and 8 of MMCAI had an area under curve (95% confidence intervals) to predict 30-day mortality of 0.77 (0.66-0.87; p < .001), 0.82 (0.69-0.91; p < .001) and 0.85 (0.72-0.94; p < .001) respectively. CONCLUSIONS The two new findings of our study are that non-surviving MMCAI patients showed higher serum substance P levels at day 1, 4 and 8 than surviving, and that those levels could predict 30-day mortality.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, Santa Cruz de Tenerife 38010, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Tenerife, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
| | - Mónica Argueso
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez n°17-19, Valencia 46004, Spain
| | - Luis Ramos
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma 38713, Spain
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain.
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain.
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
| | - Victor García-Marín
- Department of Neurosurgery, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320 Santa Cruz de Tenerife, Spain
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Miao X, Zhou T, Zhang J, Xu J, Guo X, Hu H, Zhang X, Hu M, Li J, Yang W, Xie J, Xu Z, Mou L. Enhanced cell selectivity of hybrid peptides with potential antimicrobial activity and immunomodulatory effect. Biochim Biophys Acta Gen Subj 2020; 1864:129532. [PMID: 31953126 DOI: 10.1016/j.bbagen.2020.129532] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 12/20/2019] [Accepted: 01/13/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. METHODS Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. RESULTS Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in α-helix content and the interruption in α-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-κB phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-κB phosphorylation and TNF-α expression. CONCLUSION Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.
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Affiliation(s)
- Xiaokang Miao
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Tianxiong Zhou
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China
| | - Jingying Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Jingjie Xu
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China
| | - Xiaomin Guo
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China
| | - Hui Hu
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China
| | - Xiaowei Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Mingning Hu
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China
| | - Jingyi Li
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Wenle Yang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Junqiu Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Zhaoqing Xu
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, PR China
| | - Lingyun Mou
- Institute of Biochemistry and Molecular Biology, School of Life Science Lanzhou University, Lanzhou 730000, PR China.
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Tachykinins and Kisspeptins in the Regulation of Human Male Fertility. J Clin Med 2019; 9:jcm9010113. [PMID: 31906206 PMCID: PMC7019842 DOI: 10.3390/jcm9010113] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 12/21/2022] Open
Abstract
Infertility is a global disease affecting one out of six couples of reproductive age in the world, with a male factor involved in half the cases. There is still much to know about the regulation of human male fertility and thus we decided to focus on two peptide families that seem to play a key role in this function: tachykinins and kisspeptins. With this aim, we conducted an exhaustive review in order to describe the role of tachykinins and kisspeptins in human fertility and their possible implications in infertility etiopathogenesis. Many advances have been made to elucidate the roles of these two families in infertility, and multiple animal species have been studied, including humans. All of this knowledge could lead to new advances in male infertility diagnosis and treatment, but further research is needed to clarify all the implications of tachykinins and kisspeptins in fertility.
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50
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Histomorphology of Seminal Vesicles Subsequent to Exogenous Neurokinin B Administration in New Zealand White Rabbits. Int J Pept Res Ther 2019. [DOI: 10.1007/s10989-019-10001-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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