scholarly journals P2-receptors as promising target for future drugs

2016 ◽  
Vol 97 (1) ◽  
pp. 135-141
Author(s):  
A U Ziganshin
Keyword(s):  
P2 Receptors ◽  
New Drugs ◽  
Internal Organs ◽  
Promising Target ◽  
Pathophysiological Role ◽  
Specific Receptors ◽  
Medical University ◽  
Near Future ◽  
University Laboratory

Now it is recognized that extracellular adenosine triphosphate (ATP), along with certain other purine and pyrimidine compounds is capable to regulate many intracellular processes by affecting specific receptors - P2-receptors. These receptors are widely distributed in the organs and tissues of humans and animals. It has been shown that P2-receptors are involved in the vascular tone maintenance, nerve transmission modulation, hemostasis regulation and functions of many internal organs. P2-receptors wide variety and broad representation makes them very attractive as potential targets for new drugs with the original mechanism of action. About 20 years ago in the Kazan State Medical University laboratory was created and research group on studying the fundamental and applied aspects of the P2-receptors was formed. Professor A.U. Ziganshin, a disciple and colleague of professor G. Burnstock, leads this group. In this article, an overview of research carried out by the author or under his supervision over the past two decades to study the physiological and pathophysiological role of P2-receptors in humans and animals, as well as the evaluation of these receptors as potential targets for action of new drugs, is given. In particular, it describes the work to identify new and effective P2-receptors antagonists, the role and characteristics of ecto-ATPase activity in different tissues are described, an overview of studies to assess the unique hypersensitivity of P2-receptors at low temperatures is given. Also studies on assessing the presence and functional role of P2-receptors in the pregnant human uterus, inflamed fallopian tubes, various blood vessels are presented in summary form. Obviously, due to the growing interest of many pharmaceutical companies to this area, in the near future we can expect new drugs, which are P2-receptors agonists or antagonists and are effective in treatment of various human diseases.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2020 ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Weijin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Virus Entry ◽  
Cathepsin L ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

SUMMARYTo discover new drugs to combat coronavirus disease 2019 (COVID-19), an understanding of the molecular basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated and was positively correlated with disease course and severity in COVID-19 patients. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cell lines and human ACE2 transgenic mice, while CTSL overexpression, in turn, enhanced pseudovirus infection. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity and prevented SARS-CoV-2 pseudovirus infection. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

Overview of Biological Therapy in Ulcerative Colitis: Current and Future Directions

2015 ◽  
Vol 24 (2) ◽  
pp. 203-213 ◽  
Author(s):  
Federica Furfaro ◽  
Cristina Bezzio ◽  
Sandro Ardizzone ◽  
Alessandro Massari ◽  
Roberto De Franchis ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Immunosuppressive Agents ◽  
Mucosal Healing ◽  
Aminosalicylic Acid ◽  
Proinflammatory Mediators ◽  
Experimental Drugs ◽  
New Treatments ◽  
Aggressive Clinical Course ◽  
Near Future

The treatment of ulcerative colitis (UC) has changed over the last decade. It is extremely important to optimize the therapies which are available nowadays and commonly used in daily clinical practice, as well as to stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. Therefore, it is mandatory to identify the patients' prognostic variables associated with an aggressive clinical course and to test the most potent therapies accordingly.To date, the conventional therapeutic approach based on corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid) or immunosuppressive agents is commonly used as a first step to induce and to maintain remission. However, in recent years, knowledge of new pathogenetic mechanisms of ulcerative colitis have allowed us to find new therapeutic targets leading to the development of new treatments that directly target proinflammatory mediators, such as TNF-alpha, cytokines, membrane migration agents, cellular therapies.The aim of this review is to provide the most significant data regarding the therapeutic role of drugs in UC and to give an overview of biological and experimental drugs that will become available in the near future. In particular, we will analyse the role of these drugs in the treatment of acute flare and maintenance of UC, as well as its importance in mucosal healing and in treating patients at a high risk of relapse.

Potential Role of Cytokines in Children with Acute Appendicitis and Acute Mesenteric Lymphadenitis

2011 ◽  
Vol 11 (1) ◽  
pp. 130-133
Author(s):  
Astra Zviedre ◽  
Arnis Engelis ◽  
Mohit Kakar ◽  
Aigars Pētersons
Keyword(s):  
Early Detection ◽  
Acute Appendicitis ◽  
Inflammatory Mediators ◽  
Potential Role ◽  
Clinical Symptoms ◽  
Future Research ◽  
Mesenteric Lymphadenitis ◽  
Proper Diagnosis ◽  
Near Future

Potential Role of Cytokines in Children with Acute Appendicitis and Acute Mesenteric Lymphadenitis Although, AAP and AML have different etiological factors, clinical symptoms are very much similar but treatment tactics in both the disease differ a lot. In case of AML, treatment is more conservative and does not require hospitalization while in case of AAP immediate hospitalization and maybe further surgery can be mandatory. With the identification of group of cytokines serum inflammatory mediators IL-8, IL-10, IL-12[p70], IL-17, TNF-a and MCP-1, it is believed early and proper diagnosis of AAP in the near future. Research of cytokines-serum inflammatory mediators has opened new opportunities for an early detection and differentiation of these two diseases in children.

A Comparative Study of 1D Descriptors Supported CoMFA and CoMSIA QSAR Models to Gain Novel Insights into 1,2,4-Triazoles Acting As Antitubercular Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Rajdeep Ray ◽  
Gautham Shenoy ◽  
N V Ganesh Kumar Tummalapalli
Keyword(s):  
External Validation ◽  
Antitubercular Activity ◽  
New Drugs ◽  
Rational Approach ◽  
Antitubercular Drugs ◽  
Comfa Model ◽  
Qsar Models ◽  
Structural Insights ◽  
The Way

: Tuberculosis is one of the leading cause for deaths due to infectious disease worldwide. There is an urgent need for developing new drugs due to the rising incidents of drug resistance. Triazoles have previously been reported to show antitubercular activity. Various computational tools pave the way for a rational approach in understanding the structural importance of these compounds in inhibiting Mycobacterium tuberculosis growth. The aim of this study is to develop and compare two different QSAR models based on a set of previously reported molecules and use the best one for gaining structural insights in to the Triazole molecules. In the current study, two separate models were generated with CoMFA and CoMSIA descriptors respectively based on a dataset of triazole molecules showing antitubercular activity. Several one dimensional (1D) descriptors were added to each of the models and the validation results and the contour data generated from them were compared. The best model was studied to give a detailed understanding of the triazole molecules and their role in the antitubercular activity.The r2, q2, predicted r2 and SEP (Standard error of prediction) for the CoMFA model were 0.866, 0.573, 0.119 and 0.736 respectively and for the CoMSIA model the r2, q2, predicted r2 and SEP were calculated to be 0.998, 0.634, 0.013 and 0.869 respectively. Although both the QSAR models produced acceptable internal and external validation scores but the CoMSIA results were significantly better. The CoMSIA contours also provided a better match than CoMFA with most of the features of the active compound 30b. Hence, the CoMSIA model was chosen and its contours were explored for gaining structural insights on the triazole molecules. The CoMSIA contours helped us to understand the role of several atoms and groups of the triazole molecules in their biological activity. The possibilities for substitution in the triazole compounds that would enhance the activity were also analysed. Thus, this study paves the way for designing new antitubercular drugs in future.

A Review on Ethnobotanical, Phytochemical, Pharmacological and Traditional Aspects of Indigenous Indian Herb Trachyspermum ammi (L)

2020 ◽  
Vol 6 (3) ◽  
pp. 172-187 ◽  
Author(s):  
Nikita Saraswat ◽  
Neetu Sachan ◽  
Phool Chandra
Keyword(s):  
Chemical Constituents ◽  
Collective Data ◽  
Trachyspermum Ammi ◽  
Present Information ◽  
Gastrointestinal Problems ◽  
Vedic Literature ◽  
Key Terms ◽  
Phytochemical Studies ◽  
Near Future

Introduction and Ethnopharmacological relevance: In the Indian Vedic literature, Charakasamhita and Sushritasamhita, the Ajwain is known as Bhootika and in the charaksamhita commentaries, it is termed as Yavanika. The medicinal role of Ajwain fruit is claimed to be very important in the treatment of many ailments in humans. The plant Trachyspermum ammi Linn. is a grassy, aromatic annual plant, which falls in the family Umbelliferae. This plant is grown in India, Iran, Pakistan, Egypt, etc. for its medicinal benefits. Tribals of India use it for the treatment of diarrhea, arthritis, colic and gastrointestinal problems. In the traditional preparations, Indian Vaidya guru’s (Ayurveda Guru’s), the ajwain extract is used as “Admoda Arka”. The Ayurveda doctors, hakims and Vaidya gurus recommend ajwain for treating headaches, cold, flu and even during painful menstrual periods. Aim of the Study: The review paper has compiled the researches conducted on Trachyspermum ammi, which will help in presenting a collective data of the authentic researches conducted on the plant worldwide. It will also present information about the phytoconstituents which can be useful for building up new researches in near future. Materials and Methods: This paper has been prepared by collecting all the information available on the following platforms and the papers were searched from 1975 to 2019. The databases and electronic journals were well searched including Wiley, Springer link, Google Scholar, Science Direct, Pubmed. The key terms used for the search were Ajwain, C. copticum, Trachyspermum ammi and other synonyms of the plant. The search was also done by the names of chemical constituents present in the plant and the pharmacological effect of the plant. Results: The multiple uses of T. ammi are due to the active constituents present in it. As per the phytochemical studies on the fruits of T. ammi, the presence of various phytoconstituents has been found such as saponins, flavonoids, alkaloids, glycosides, fixed oils, thymenes, cumenes, tannins, amino acids, p-cymene, c-terpinene, steroids, etc. Conclusions: This paper is focused on presenting a detailed review on the literature, pharmacological properties, physicochemical studies and the newest researches on the plant. In this paper, we have also compiled the traditional uses of the herb used by Indian peopleon recommendations from their Hakims, Vaidya and use of the herbs by many tribes all across India and Pakistan.

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