montelukast and Diabetes-Mellitus--Type-2

Increasing the affinity of diamidines for AT-rich regions of DNA has long been an important goal of medicinal chemists who wanted to improve the antiparasitic and antifungal properties of that class of derivatives. In recent years it was demonstrated that diamidines could interfere with many other biomolecular targets including ion channels as well as enzymes and modulate some RNA-protein, DNA-protein, and protein-protein interactions. It is therefore not surprising that diamidines now emerge as novel potential drug candidates for the treatment of various diseases, i.a. neurodegenerative disorders, acidosis-related pathological conditions, hypertension, thrombosis, type 2 diabetes, myotonic dystrophy, and cancers. A summary of the most striking results obtained to date in those domains is presented is this review.

Topics: Amidines; Animals; Diabetes Mellitus, Type 2; DNA; Enzymes; Humans; Hypertension; Ion Channels; Myotonic Dystrophy; Neoplasms; Neurodegenerative Diseases; Proteins; RNA; Thrombosis

To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD).. A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers.. A United States Department of Veterans Affairs Health Care System outpatient setting.. Adults with type 2 diabetes and asthma or COPD.. Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 microg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value.. Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and -0.14, respectively).. The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Anti-Asthmatic Agents; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Fluticasone; Glucose; Glycated Hemoglobin; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quinolines; Sulfides; Treatment Outcome

Direct critical attack of the coronavirus on the alveoli and the excessive release of a large number of cytokines (IL-6, IL-1, TNF-α, etc.) provides suitable conditions for the further development of acute respiratory distress syndrome (ARDS) and severe acute respiratory failure. Serious decrease in blood oxygenation often lead to the deterioration of macro- and microcirculation, irreversible brain damage and hence, persistent neurological and mental disorders despite background intensive therapy and adequate respiratory support. Therefore, the aim of our open prospective observational study was to investigate the neuroprotective and antioxidant effectiveness of montelukast-acetylcysteine combination therapy for brain protection in patients with COVID-19 viral pneumonia. A study was performed for five hundred seventy-eight (n=578) outpatients who were tested positive for novel coronavirus (SARS-CoV-2) by nasopharyngeal swap. The median age of patients was 62±17.45 years. In addition to clinical features and RT-PCR results, chest CT and chest X-ray (CXR) with high sensitivity were also very helpful for the early identification of viral pneumonia and COVID-19 disease assessment. Considering the severity of Covid-19 pneumonia and the level of arterial oxygen saturation (transcutaneous hemoglobin oxygen saturation) on room air, all patients were divided into three major groups. Group 1 (n=288) consisted of patients with a mild shift in oxygen saturation (SpO2 ≥ 95%) and well-defined pulmonary lesions (within 1-2 segments) without concomitant diseases; the second group (Group 2, n=250) included patients with clinical manifestations of moderate severity associated with a current saturation of 90-95% (SpO2) and small pulmonary lesions on chest X-ray in the presence of concomitant diseases: arterial hypertension (stage III) or CHF (FC/NYHA-2), coronary heart disease or type 2 diabetes, cancer, tuberculosis, etc. Most of the patients in third group (Group 3, n=48), during imaging studies, showed bilateral lung affection with low and peripheral distribution (with both - either ground glass opacities or multiple pulmonary nodules) and cardiomegaly. The respiratory failure of stage II-III (current oxygen saturation SpO2 75-90%), high respiratory rate (≥25 per minute), hemodynamic impairment (BP≤100/60 mm Hg. Art., heart rate ≥125/min) were the most common objective clinical findings seen in this subset of patients. Laboratory changes included leukopenia less than 4.0

Topics: Acetylcysteine; Adult; Aged; Antioxidants; COVID-19; Diabetes Mellitus, Type 2; Humans; Interleukin-6; Microcirculation; Middle Aged; Oxygen; Pneumonia, Viral; Respiratory Distress Syndrome; SARS-CoV-2

Montelukast (MNK), a leukotriene receptor antagonist, has proven its antioxidant/anti-inflammatory capacity to guard against diabetes-induced complications and to enhance metformin antidiabetic effect. Nevertheless, here we evaluated the involvement of endoplasmic reticulum (ER) stress and insulin signaling cascade in the effect of MNK and/or dapagliflozin (DAPA) using the soleus muscle of type 2 diabetic (T2D)/insulin resistant (IR) rats.. To induce T2D/IR, rats were fed a westernized diet (WD) for 8 weeks followed by a sub-diabetogenic dose of streptozotocin (STZ). Animals were divided into control (receiving normal diet; ND), diabetic untreated, and diabetic treated for 4 weeks with DAPA, MNK, or their combination (DAPA+MNK). Blood glucose and serum lipid profile were determined, and the soleus muscle was tested for ER stress-induced IR, besides histopathological examination.. Treatment with DAPA, MNK, and especially their combination decreased the fasting plasma levels of glucose and insulin while improving insulin sensitivity and lipid profile. This was achieved via the activation of insulin signaling IRS-1/AKT/GLUT4 pathway in the soleus muscle consequent to the deactivation of the ER stress response elements, namely IRE1α, ATF6, and PERK to suppress p-JNK and p-eIF2α.. Improved insulin signaling along with the deactivation of the ER stress response by MNK comparable to the DAPA are partly responsible for the enhanced soleus muscle insulin sensitivity, effects that nominate MNK as an add-on to DAPA to enhance its antidiabetic efficacy.

Topics: Acetates; Animals; Antioxidants; Benzhydryl Compounds; Blood Glucose; Cyclopropanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Endoribonucleases; Glucose Transporter Type 4; Glucosides; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leukotriene Antagonists; Metformin; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Quinolines; Rats; Response Elements; Streptozocin; Sulfides

Insulin resistance is an important pathological hallmark of type 2 diabetes mellitus. Glucose-stimulated insulin secretion (GSIS) plays a key role in maintaining blood glucose levels within normal range. Impaired GSIS has been associated with type 2 diabetes, however, the underlying molecular mechanisms remain largely unknown. Cysteinyl leukotriene receptor 1 (cysLT1R) is an important G protein-coupled receptor mediating the biological functions of cysteinyl leukotrienes (cys-LTs). Little is known about the effects of cysLT1R in insulin secretion and pathogenesis of T2DM. In the present study, we aimed to define the physiological functions of cysLT1R in GSIS in MIN6 β-cells. Using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, we found that cysLT1R was expressed in pancreatic MIN6 β-cells. We also reported that glucose increased the expression of cysLT1R in MIN6 cells. Additionally, the cysLT1R antagonist montelukast promoted GSIS in a dose dependent manner, however, the cysLT1R agonist LD4 inhibited GSIS, suggesting an antagonistic effect of cysLT1R on GSIS. Silencing of cysLT1R by transfection with cysLT1R siRNA enhanced GSIS while overexpression of cysLT1R reduced GSIS in pancreatic MIN6 β-cells. Mechanistically, we found that the Arf6/Cdc42/Rac1 pathway was involved in this process. Collectively, our findings highlight the essential role of cysLT1R in suppressing pancreatic insulin secretion, and potentially provided a new insight into understanding the mechanical regulation of glucose homeostasis.

Topics: Acetates; ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Animals; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cyclopropanes; Cysteine; Diabetes Mellitus, Type 2; Glucose; Insulin Secretion; Insulin-Secreting Cells; Leukotrienes; Mice; Neuropeptides; Quinolines; rac1 GTP-Binding Protein; Receptors, Leukotriene; Sulfides