Indazole Derivatives Effective against Gastrointestinal Diseases

2021 ◽  
Vol 21 ◽  
Author(s):  
Supriyo Saha ◽  
Dilipkumar Pal ◽  
Satish Balasaheb Nimse
Keyword(s):  
Metabolic Syndrome ◽  
Critical Role ◽  
Gastrointestinal Diseases ◽  
Aromatic Acid ◽  
Gastrointestinal Disorders ◽  
Amino Acid Residues ◽  
Alkyl Aryl ◽  
Plot Analysis ◽  
One Step ◽  
Treatment Of Diabetes

Background: In this fast-growing lifestyle, humans are in the race against time to cope up with busy schedule. Less exercise, consumption of high calorie-low fiber food and stress take us one step closer towards digestive dysfunction. Dysfunctional digestive system causes various gastrointestinal disorders like constipation, IBS, UC, diarrhea, gastrointestinal tract immobility, hyperglycemia, hemorrhoids, fistula, anal fissures, stomach cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer and metabolic syndrome. Amongst various natural and synthetic indazole derivatives nigellicine, nigellamine, nigellidine, zanubrutinib and SCH772984 showed prominent results to cure various gastrointestinal disorders. Objective: In this manuscript, we focus on the importance of indazole derivatives in the treatment of various gastrointestinal diseases. Results and Conclusion: In the treatment of IBS, four positions (R1, R2, R3 and R4) of indazole were mainly substituted with aromatic aldehyde/substituted methyl, aromatic acid/formamide, benzamide/sulfonamide and methyl groups, respectively. In case of diarrhea and metabolic syndrome treatment, substitutions with benzyl/isopropyl/acetaldehyde (R1 position) and carboxamide/formamide (R2 position) of indazole play a critical role. Also, in the treatment of diabetes melitus, all six positions of indazole derivative were substituted with substituted aryl/alkyl/aromatic acid, substituted formamide, substituted acetamide/hydrazide group, halo aryl, substituted aryl/aromatic acid and a long chain of alkyl-aryl alcohol groups, respectively. In the treatment of gastrointestinal cancers, all six positions of indazole derivative were substituted with benzylamide (R1), octanediamide/benzamide/formamide (R2), carbaldehyde (R4) and substituted phenyl (R5 and R6) groups, respectively. Six receptors (6NP0, 2YME, 4EFU, 4WZ8, 5U4W and 7KKP) associated with GI disorders (co-crystallized with indazole derivative) were identified. Analysis of the receptors showed that co-crystalized ligand molecules were well-interacted with receptors via pie-pie interaction, co-ordinate and sigma bonding within 4 Å distance. As per Ramachandran plot analysis, more than 90% of the amino acid residues were present in the most favored region. So, if sufficient focuses are imposed on the development of newer indazole derivatives to treat gastrointestinal diseases, it will work as a boon to society.

scholarly journals The Spindle Checkpoint of the Yeast Saccharomyces cerevisiae Requires Kinetochore Function and Maps to the CBF3 Domain

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1493-1502
Author(s):  
Richard D Gardner ◽  
Atasi Poddar ◽  
Chris Yellman ◽  
Penny A Tavormina ◽  
M Cristina Monteagudo ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Critical Role ◽  
Spindle Checkpoint ◽  
Essential Genes ◽  
Gene Fusions ◽  
Yeast Saccharomyces Cerevisiae ◽  
Checkpoint Signaling ◽  
One Step ◽  
Diploid Cells ◽  
Kinetochore Function

Abstract We have measured the activity of the spindle checkpoint in null mutants lacking kinetochore activity in the yeast Saccharomyces cerevisiae. We constructed deletion mutants for nonessential genes by one-step gene replacements. We constructed heterozygous deletions of one copy of essential genes in diploid cells and purified spores containing the deletion allele. In addition, we made gene fusions for three essential genes to target the encoded proteins for proteolysis (degron alleles). We determined that Ndc10p, Ctf13p, and Cep3p are required for checkpoint activity. In contrast, cells lacking Cbf1p, Ctf19p, Mcm21p, Slk19p, Cse4p, Mif2p, Mck1p, and Kar3p are checkpoint proficient. We conclude that the kinetochore plays a critical role in checkpoint signaling in S. cerevisiae. Spindle checkpoint activity maps to a discreet domain within the kinetochore and depends on the CBF3 protein complex.

SATP (YaaH), a succinate–acetate transporter protein in Escherichia coli

2013 ◽  
Vol 454 (3) ◽  
pp. 585-595 ◽  
Author(s):  
Joana Sá-Pessoa ◽  
Sandra Paiva ◽  
David Ribas ◽  
Inês Jesus Silva ◽  
Sandra Cristina Viegas ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Acetic Acid ◽  
Succinic Acid ◽  
Critical Role ◽  
Amino Acid Residues ◽  
E Coli ◽  
Transporter Protein ◽  
Affinity Constants ◽  
In Trans

In the present paper we describe a new carboxylic acid transporter in Escherichia coli encoded by the gene yaaH. In contrast to what had been described for other YaaH family members, the E. coli transporter is highly specific for acetic acid (a monocarboxylate) and for succinic acid (a dicarboxylate), with affinity constants at pH 6.0 of 1.24±0.13 mM for acetic acid and 1.18±0.10 mM for succinic acid. In glucose-grown cells the ΔyaaH mutant is compromised for the uptake of both labelled acetic and succinic acids. YaaH, together with ActP, described previously as an acetate transporter, affect the use of acetic acid as sole carbon and energy source. Both genes have to be deleted simultaneously to abolish acetate transport. The uptake of acetate and succinate was restored when yaaH was expressed in trans in ΔyaaH ΔactP cells. We also demonstrate the critical role of YaaH amino acid residues Leu131 and Ala164 on the enhanced ability to transport lactate. Owing to its functional role in acetate and succinate uptake we propose its assignment as SatP: the Succinate–Acetate Transporter Protein.

scholarly journals Eosinophilic Gastrointestinal Diseases: Review and Update

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Mahreema Jawairia ◽  
Ghulamullah Shahzad ◽  
Paul Mustacchia
Keyword(s):  
Gastrointestinal Tract ◽  
Clinical Features ◽  
Gastrointestinal Symptoms ◽  
Gastrointestinal Diseases ◽  
Gastrointestinal Disorders ◽  
Diverse Group ◽  
Intestinal Diseases ◽  
Gastrointestinal Inflammation ◽  
Eosinophilic Gastrointestinal Disorders

Eosinophilic gastrointestinal disorders (EGIDs) are a progressively more frequent diverse group of intestinal diseases. The intention of this paper is to present the newest developments in the care of patients with EGIDs and to sum up a rising literature defining the clinical features and mechanistic elements of eosinophils and their intricate associations with the gastrointestinal tract. Clinicians ought to stay sensitive to EGIDs as a diagnostic likelihood for patients with general gastrointestinal symptoms. Further research is warranted to establish various methods leading to dysfunction coupled with eosinophilic gastrointestinal inflammation.

scholarly journals Abdominal syndrome in pulmonary tuberculosis

2021 ◽  
Vol 30 (9) ◽  
pp. 839-843
Author(s):  
N. M. Zakharov
Keyword(s):  
Gastrointestinal Tract ◽  
Pulmonary Tuberculosis ◽  
Digestive System ◽  
Diagnostic Errors ◽  
Gastrointestinal Diseases ◽  
The Other ◽  
Gastrointestinal Disorders ◽  
System Function ◽  
Anatomical Changes ◽  
The Subject

A large number of works that have appeared in recent years in our and foreign literature on the subject of tuberculous intestinal diseases can be explained mainly by the exceptional importance of the gastrointestinal tract behavior in tbc patients and, on the other hand, by the frequency of this suffering. Most of these works concern the clinic of tuberculous lesions of the intestine with a definite pathological and anatomical substrate at the base. However, disorders of digestive system function in patients with pulmonary tuberculosis can occur without the presence of any anatomical changes and dyspeptic disorders observed in these cases, extremely diverse in their clinical picture, not seldom present exceptional difficulty in recognizing the true causes of gastrointestinal disorders. Passing under the mask of a variety of gastrointestinal diseases, they can give rise to diagnostic errors.

scholarly journals Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes

Gut ◽  
1998 ◽  
Vol 42 (5) ◽  
pp. 643-649 ◽  
Author(s):  
M Carol ◽  
A Lambrechts ◽  
A Van Gossum ◽  
M Libin ◽  
M Goldman ◽  
...  
Keyword(s):  
Lamina Propria ◽  
Intestinal Mucosa ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Gastrointestinal Diseases ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

Background—Cytokines secreted by intestinal T lymphocytes probably play a critical role in regulation of the gut associated immune responses.Aims—To quantify interferon γ (IFN-γ) and interleukin 4 (IL-4) secreting cells (SC) among human intraepithelial (IEL) and lamina propria (LPL) lymphocytes from the duodenum and right colon in non-pathological situations and in the absence of in vitro stimulation.Patients—Duodenal and right colonic biopsy specimens were obtained from patients with no inflammation of the intestinal mucosa.Methods—Intraepithelial and lamina propria cell suspensions were assayed for numbers of cells spontaneously secreting IFN-γ and IL-4 by a two site reverse enzyme linked immunospot technique (ELISPOT).Results—The relatively high proportion of duodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL 1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very low numbers of spontaneously IFN-γ SC and the absence of spontaneously IL-4 SC among peripheral blood mononuclear cells. In the basal state, both IFN-γ and IL-4 were mainly produced by CD4+ cells. Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in the basal state, and 0.1% secreted IL-4.Conclusions—Compared with peripheral lymphocytes substantial proportions of intestinal epithelial and lamina propria lymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokines are probably involved in the normal homoeostasis of the human intestinal mucosa. Disturbances in their secretion could play a role in the pathogenesis of gastrointestinal diseases.

OBESITY: CLINICAL AND PATHOGENETIC JUSTIFICATION OF PREVENTION AND TREATMENT

2020 ◽  
pp. 5-10
Author(s):  
O. M. Korzh
Keyword(s):  
Metabolic Syndrome ◽  
Antihypertensive Drugs ◽  
Critical Role ◽  
Cardiovascular Complications ◽  
Excess Body Weight ◽  
Treatment And Prevention ◽  
Prevalence Of Obesity ◽  
Tissue Sensitivity ◽  
Genetic And Environmental Factors ◽  
Weight Correction

Obesity is one of the most common chronic diseases worldwide. Numerous studies in recent years have identified obesity as a key cause of type 2 diabetes, metabolic syndrome, and cardiovascular disease. Comprehensive medical and non−medical treatment of metabolic disorders, obesity and correction of excess body weight are the urgent tasks for both the patient and doctor. When defining the obesity as a chronic psychosomatic disease caused by the interaction of numerous genetic and environmental factors there is emphasized the complexity of the problem, including psychological, medical, social, physical and economic aspects. The widespread prevalence of obesity, which determines its comorbid nature, dictates the need to clarify the principles and options for treatment and prevention. In the process of active study, the multicomponent pathogenesis of obesity with the important role of different parts of the brain determines the relevance of a combination of pharmacotherapy and lifestyle intervention. In pharmacotherapy, the weight correction is an important component and reduces the risk of cardiovascular complications, improves quality of life and prognosis. The basis of weight correction measures is a change in lifestyle, increased physical activity and alteration in diet in order to achieve a balance between energy consumption and expenditure. Weight loss is accompanied with an increased tissue sensitivity to insulin, improved lipid metabolism, elimination of latent inflammation, lowering blood pressure and, accordingly, plays a critical role in prevention of the associated diseases and reducing the risk of complications. The fight against obesity is not only an improvement in the patient general condition, but also a great economic benefit, as the doses of drugs are reduced or the need for hypolipidemic, antidiabetic and antihypertensive drugs disappears. Key words: obesity, metabolic syndrome, diabetes mellitus, cardiometabolic risk, microbiota, insulin resistance, treatment, prevention.

scholarly journals Understanding value creation in cultural industries: strategies for creating and managing meaning

2020 ◽  
Vol 2 (3) ◽  
pp. 165-180
Author(s):  
Eden Yin ◽  
Nelson Phillips
Keyword(s):  
Value Creation ◽  
Critical Role ◽  
Selection System ◽  
Cultural Products ◽  
Content Type ◽  
Product Categories ◽  
Collective Creativity ◽  
Selection Systems ◽  
One Step ◽  
Entire Society

Purpose This paper aims to analyse the valuation of cultural products and explores what this process means for organizations involved in their production and marketing. Design/methodology/approach The authors develop the arguments using a number of mini-cases and industry examples. Findings The main thesis is that the meaningfulness and value ambiguity of cultural products shift the focus of valuation away from the products themselves towards how certain agents in the socio-cultural environment identify and certify these products. This paper discuss how valuation takes place via selection systems and how the nature of cultural products drives the dominance of one selection system over others. Research limitations/implications Theories on value creation needs to take consideration of the critical role played by the selection system instead of just the firms that produce these products. Practical implications Organizations engaged in producing highly symbolic products need to manage selection systems and related industry dynamics to establish an enduring competitive advantage. Social implications Value creation is a collective social efforts. Every member of the society can play a central role in this process. Better engaging various member of the society to enable them actively participate in the value creation process is what organizations today need to consider, instead of just treating individuals in the society as a “customer” who only passively consume. This research calls for the true empowerment of every member of the society to facilitate collective creativity and participation in the value creation endeavour that benefits the entire society as a whole. Originality/value It is the first paper that has created a conceptual link between the type of selection system and product categories. In other words, it takes existing literature on value creation and selection system one step further by creating the alignment or match between types of selection system and types of product categories. Therefore, it offers academics and practitioners a much detailed understanding on how value creation is conducted across different product categories.

scholarly journals Efficacy and Safety of Hou Gu Mi Xi on Spleen Qi Deficiency in Patients with Nonorganic Gastrointestinal Disorders: Protocol for a Multicenter, Randomized, Placebo-Controlled Trial

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Xiaofan Chen ◽  
Heyun Nie ◽  
Wenjun Liu ◽  
Xu Zhou ◽  
Jianhua Nie ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Gastrointestinal Diseases ◽  
Ethics Committee ◽  
Gastrointestinal Disorders ◽  
Evidence Based ◽  
Research Model ◽  
Efficacy And Safety ◽  
Medical Treatments ◽  
Study Population ◽  
Double Blinded

Background. There is a worldwide epidemic of nonorganic gastrointestinal disorders (NOGDs), which are a class of disorders that cause various discomforts and ultimately progress into organic gastrointestinal diseases. Because of the unsatisfactory efficacy of Western medical treatments, traditional Chinese medicine (TCM) is becoming a promising complementary and alternative treatment to manage NOGDs. Objectives. To investigate the efficacy and safety of Hou Gu Mi Xi (HGMX), a newly developed dietary TCM formula, on the syndrome of spleen qi deficiency (SQD) in patients with NOGDs. Methods/Design. This study is a multicenter, randomized, double-blinded, parallel, and placebo-controlled trial that will last for 2 years. All qualified subjects with NOGDs and SQD will be included. The study population will be divided into the HGMX and placebo groups. To assess the efficacy of HGMX, we will mainly focus on changes in SQD symptoms scored by a Spleen Qi Deficiency Symptoms Grading and Quantifying Scale and evaluate changes in gastrin-17, the negative Helicobacter pylori conversion rate, body weight, body mass index, and gastroscopy findings. The safety of HGMX will be assessed by recording adverse events (AEs), severe AEs, treatment-related AEs and withdrawal due to AEs. Discussion. This trial is part of our study series that intends to validate the potential of HGMX in the management of chronic gastrointestinal diseases. This series of RCTs is the first committed to the evaluation of a dietary TCM formula and will hopefully establish an evidence-based clinical research model for dietary TCM formulas. Ethics. The protocol was approved by Ethics Committee of five research hospitals and was registered in Clinicaltrials.gov (NCT03019042).

Definition of Essential Amino Acid Residues in the Recognition of a Peptide by a Mouse Monoclonal Antibody

1997 ◽  
Vol 52 (3-4) ◽  
pp. 274-278
Author(s):  
Laura Rosanó ◽  
Francesca Di Modugno ◽  
Giulia Romagnoli ◽  
Alberto Chersi
Keyword(s):  
Monoclonal Antibody ◽  
Amino Acid ◽  
Critical Role ◽  
Binding Activity ◽  
Mouse Monoclonal Antibody ◽  
Amino Acid Residues ◽  
Binding Data ◽  
Amino Acid Stretch ◽  
Definition Of ◽  
Key Residues

AbstractA mouse monoclonal antibody reacting in ELISA with a synthetic peptide representing a linear amino acid stretch of the protein antigen was tested on all overlap­ ping 5-mer to 9-mer fragments of the peptide, as prepared by multi-pin synthesis. Analysis of the binding data suggests that several residues in the peptide might be relatively unrelevant for recognition, while few others seem to play a critical role as key residues. On the basis of such observations, we attempted to reconstruct an alternative essential epitope by introducing multiple amino acid substitutions in the 9-mer peptide exhibiting the best binding activity, and then tested its ability to be recognized by the monoclonal antibody.

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