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... In this regard, a decrease in vasorelaxation to Ang-(1-7) and an increase in Ang II-induced contractile responses have been reported in metabolic diseases, including insulin resistance (Karpe and Tikoo, 2014;Viswanad et al., 2006), metabolic syndrome (Ghatta and Ramarao, 2004) and diabetes (Pernomian et al., 2014). According to this, our results show that vascular responses to Ang-(1-7) are significantly decreased during STZ-induced HG probably due to: 1) changes in the expression of receptors and enzymes that J o u r n a l P r e -p r o o f favour signalling pathways and production of these peptides (Pernomian et al., 2014;Qiao et al., 2015); 2) an increase in reactive oxygen species (Pernomian et al., 2012;Xu et al., 2022) and 3) a lower NO production rate, since Ang-(1-7) ...
... In the same line of evidence, a previous study showed that contractile responses to Ang II decreased in mesenteric from diabetic animals (Chin et al., 2007). Although we have no clearcut explanation for this finding, the differences observed in the Ang II-mediated contractile responses under metabolic conditions could be mediated by: 1) changes in the expression of angiotensin II AT 1 receptor (Pernomian et al., 2012;Qiao et al., 2015); 2) changes in the expression of G proteins that affect the extent of receptor-initiated cellular signal and function (Siddiqui and Hussain, 2007); 3) ...
... Similar results have been shown in cardiac tissue from STZ-induced diabetes models (Qiao et al., 2015). Taken together, our study reveals that STZ-induced HG alters Ang-(1-7) synthesis by impairing ACE2 protein expression, which promotes a decrease in this peptide serum level. ...
Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-ץ-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n=12) or 2) streptozotocin (STZ, 70mg/kg; n=48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n=12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1mL/kg); 3) NaHS (5.6mg/kg); and 4) DL-PAG (10mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1-7) [Ang-(1-7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1-7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1-7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1-7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.
... It is therefore vital to carefully monitor the medication dosage and the duration of treatment with NSAIDs.  A study by Langhendries et al. showed that repeated acetaminophen and ibuprofen exposure in children may lead to an increase in immune deviations.  They can also inhibit the action of IL-6, which is the main inflammatory cytokine. ...
During the current SARS-CoV-2 (COVID-19) pandemic, some reports were presented based on those nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. According to this, we aimed to collate information available in published articles to identify any evidence behind these statements with the aim of helping clinicians on how best to treat patients. We could not find published conclusive evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilized in the early acute phase of infection, however, conflicting WHO (World Health Organization) evidence surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients. However, the availability of reliable information for clinicians and patients is paramount.
...  On the other hand, in a study evaluating the effect of Ibuprofen on cardiac fibrosis in a rat diabetes model, it was observed that Ibuprofen increased the expression level of angiotensin-converting enzyme 2 (ACE2).  As a result of some in vitro studies found a positive correlation between the level of ACE2 expression and the risk of coronavirus infection.  However, it is stated that NSAIDs can suppress the immune system. ...
Background: The aim of this study is to evaluate the public's interest in pain and painkillers using Google search activity in countries with the most cases before and during the COVID-19 pandemic (January 2018 - December 2021).
Methods: United States (USA), England, France, Germany, Italy, India, Spain, Russia, Brazil and Turkey, which are the countries where the Covid 19 epidemic was most intense, were determined along with the world for the analysis. The words of "Back pain", "Chest pain", "Headache", "Knee pain", "Sore throat", "Aspirin", "Ibufren" and "Paracetamol" were written into the Google Trend search engine. RapidMiner Analysis program and Microsoft Excel program were used in the statistical analysis of the data. Correlation tests were used to determine the strength of the relationship between pain regions and drugs.
Results: The terms fo "ibuprofen", "aspirin", "paracetamol" peaked in Google searches on March 15, 2020. The search frequencies of the terms of sore throat, chest pain, and headache peaked worldwide between March 15, 2020 and March 22, 2020. The strong correlations were obtained, ranging from 0.627 to 0.901 for chest pain and headache terms, and 0.629 to 0.749 for ibuprofen and paracetamol terms.
Conclusion: As a result of the research, it is seen that the frequency of searching for pain and analgesics has increased significantly during the COVID-19 period. Our data can be considered as an indicative of the increasing incidence of pain with the COVID-19 pandemic, since internet searches are a proxy for the public good.
... Cohorts were split into two enrolment periods; a pre-pandemic period where the index event occurred between November 2019 and January 2020, and a pandemic period where the index event occurred between February 2020 and October 2020 COX-2i cyclooxygenase-2 inhibitors, ns-NSAIDs non-selective non-steroidal anti-inflammatory drugs of the inflammatory process by inhibiting prostanoid biosynthesis, which theoretically might weaken immune responses against pathogens [21,22]. In diabetic rats, ibuprofen has the potential to upregulate the angiotensin-converting enzyme 2 receptor, to which the severe acute respiratory syndrome coronavirus 2 virus binds before entering host cells . However, it remains unknown whether these results can be generalised to humans. ...
We aimed to investigate whether ibuprofen use, compared with other non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), cyclooxygenase-2 inhibitors (COX-2i) or paracetamol, increases the risk of coronavirus disease 2019 (COVID-19) diagnosis or hospitalisation.
A prevalent user and active comparator cohort study.
Two US claims databases (Open Claims and PharMetrics Plus) mapped to the Observational Medical Outcomes Partnership Common Data Model.
Insured patients with a history of osteoarthritis or back pain and receiving ibuprofen, other ns-NSAIDs, COX-2i or paracetamol between 1 November, 2019 and 31 January, 2020 (study enrolment window 1) or between 1 February, 2020 and 31 October, 2020 (study enrolment window 2).
Main outcome measures:
Large-scale propensity score matching and empirical calibration were used to minimise confounding. Incidence and hazard ratios of COVID-19 diagnosis and hospitalisation according to drug/s use were estimated and pooled in the same study period across data sources using a fixed-effects meta-analysis. Index treatment episode was the primary risk evaluation window, censored at the time of discontinuation.
A total of 633,562 and 1,063,960 participants were included in periods 1 and 2, respectively, for the ibuprofen versus ns-NSAIDs comparison, 311,669 and 524,470 for ibuprofen versus COX-2i, and 492,002 and 878,598 for ibuprofen versus paracetamol. Meta-analyses of empirically calibrated hazard ratios revealed no significantly differential risk of COVID-19 outcomes in users of ibuprofen versus any of the other studied analgesic classes: hazard ratios were 1.13 (0.96-1.33) for the ibuprofen-ns-NSAIDs comparison, 1.03 (0.83-1.28) for the ibuprofen-COX-2i comparison and 1.13 (0.74-1.73) for ibuprofen-paracetamol comparison on COVID-19 diagnosis in the February 2020-October 2020 window. Similar hazard ratios were found on COVID-19 hospitalisation and across both study periods.
In patients with osteoarthritis or back pain, we found no differential risks of incident COVID-19 diagnosis or COVID-19 hospitalisation for ibuprofen users compared with other ns-NSAIDs, COX-2i or paracetamol. Our findings support regulatory recommendations that NSAIDs, including ibuprofen, should be prescribed as indicated in the same way as before the COVID-19 pandemic, especially for those who rely on ibuprofen or NSAIDs to manage chronic arthritis or musculoskeletal pain symptoms.
... Oates  found that the use of azithromycin (ranked first in SDNE's results) in conjunction with nonsurgical periodontal therapy offers greater improvements in glycemic levels. In addition, several studies  have reported some possible drugs, e.g. Ketamine, Dextromethorphan, Pramipexol, Diazepam, Ezetimibe, Ibuprofen, Rabeprazole and Cetirizine that may be related to the treatment of diabetes. ...
As one of the most vital methods in drug development, drug repositioning emphasizes further analysis and research of approved drugs based on the existing large amount of clinical and experimental data to identify new indications of drugs. However, the existing drug repositioning methods didn’t achieve enough prediction performance, and these methods do not consider the effectiveness information of drugs, which make it difficult to obtain reliable and valuable results. In this study, we proposed a drug repositioning framework termed DRONet, which make full use of effectiveness comparative relationships (ECR) among drugs as prior information by combining network embedding and ranking learning. We utilized network embedding methods to learn the deep features of drugs from a heterogeneous drug-disease network, and constructed a high-quality drug-indication data set including effectiveness-based drug contrast relationships. The embedding features and ECR of drugs are combined effectively through a designed ranking learning model to prioritize candidate drugs. Comprehensive experiments show that DRONet has higher prediction accuracy (improving 87.4% on Hit@1 and 37.9% on mean reciprocal rank) than state of the art. The case analysis also demonstrates high reliability of predicted results, which has potential to guide clinical drug development.
... NSAIDs (nonsteroidal anti-inflammatory drugs) and acetaminophen are the first-line drugs against COVID-19 headaches . Initially, the role of NSAIDS, especially ibuprofen, was contested as it increased ACE2 levels . However, it was argued to be a weak bias as the trial was on diabetic rats, and the increase in ACE2 was seen in rats' hearts only . ...
At the beginning of COVID-19 pandemic the use of NSAIDS was avoided. This was because the previous studies suggesting that NSAIDs may be associated with increased risk of complications of lower respiratory tract infections. Later on studies involved the patients who used NSAIDs for some chronic conditions and showed no additional harm among these patients. Then many studied assessed the benefit of using NSAIDs in COVID-19 patients for management of pain and fever and showed no additional risk among these patients. Key words: COVID-19; pandemic; NSAIDs Citation: Mahrous R, Abdelnasser A, Fouda R, Morsy MAAM, Mandour O. NSAIDs in COVID-19, friend or foe? Anaesth. pain intensive care 2022;27(1):119−122; DOI: 10.35975/apic.v27i1.2123 Received: May 29, 2022; Reviewed: June 28, 2022; Accepted: July 03, 2022
In response to different viral infections, including SARS-CoV-2 infection, pro-inflammatory, anti-inflammatory cytokines, and bioactive lipids are released from infected and immune cells. One of the most critical bioactive lipids is prostaglandins (PGs) which favor perseverance of inflammation leading to chronic inflammation as PGs act as cytokine amplifiers. PGs trigger the release of pro-inflammatory cytokines, activate Th cells, recruit immune cells, and increase the expression of pro-inflammatory genes. Therefore, PGs may induce acute and chronic inflammations in various inflammatory disorders and viral infections like SARS-CoV-2. PGs are mainly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) by blocking cyclooxygenase enzymes (COXs), which involve PG synthesis. NSAIDs reduce inflammation by selective or non-selective blocking activity of COX2 or COX1/2, respectively. In the Covid-19 era, there is a tremendous controversy regarding the use of NSAIDs in the management of SARS-CoV-2 infection. As well, the possible role of PGs in the pathogenesis of SARS-CoV-2 infection is not well-defined. Thus, the objective of the present study is to review the potential role of PGs and NSAIDs in Covid-19 in a narrative review regarding the preponderance of assorted views.
We tested the hypothesis that activation of the protective arm of the renin angiotensin system (RAS), the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis, corrects the vasoreparative dysfunction typically seen in the CD34(+) cells isolated from diabetic individuals. Peripheral blood CD34(+) cells from patients with diabetes were compared with those of nondiabetic controls. Ang-(1-7) restored impaired migration and nitric oxide bioavailability/cGMP in response to stromal cell-derived factor and resulted in a decrease in NADPH oxidase activity. The survival and proliferation of CD34(+) cells from diabetic individuals were enhanced by Ang-(1-7) in a Mas/phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. ACE2 expression was lower and ACE2 activators xanthenone and diminazine aceturate were less effective in inducing the migration in cells from patients with diabetes compared with controls. Ang-(1-7) overexpression by lentiviral gene modification restored both the in vitro vasoreparative functions of diabetic cells and the in vivo homing efficiency to areas of ischemia. A cohort of patients who remained free of microvascular complications despite having a history of longstanding inadequate glycemic control had higher expression of ACE2/Mas mRNA than patients with diabetes with microvascular complications matched for age, sex, and glycemic control. Thus, ACE2/Ang-(1-7)\Mas pathway activation corrects existing diabetes-induced CD34(+) cell dysfunction and also confers protection from development of this dysfunction.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is essential for maintaining normal function of the adult heart and is known to play an important role in myocardial remodeling. In the present study, we observed that heart-specific HB-EGF transgenic (TG) mice had systolic dysfunction with decreased fractional shortening (FS%), increased end-systolic diameter (LVIDs) at 5 months of age, increased heart fibrosis, and increased mRNA expression of Col1α1 and Col3α1 at 1, 3, 5 and 7 months of age compared to nontransgenic (NTG) littermates. However, the left ventricular anterior wall thickness at end-systole (LVAWs) of the TG mice was not different than the NTG mice. Phosphorylation levels of Akt, mTor and p70s6k were increased due to HB-EGF expression in TG mice compared with the NTG mice at 3 and 7 months of age. Additionally, activated Akt, mTor and p70s6k were co-localized with vimentin to cardiac fibroblasts isolated from TG mice. Furthermore, HB-EGF significantly increased phosphorylation levels of Akt, mTor and p70s6k and increased expression of type I collagen in cultured primary cardiac fibroblasts. Rapamycin (Rapa) and CRM197, inhibitors of mTor and HB-EGF respectively, could inhibit the expression of type I collagen in the cultured primary cardiac fibroblasts and Rapa suppressed interstitial fibrosis of the heart tissues in vivo. In addition, a BrdU assay showed that HB-EGF increased proliferation of cardiac fibroblasts by 30% compared with cells without HB-EGF treatment. HB-EGF-induced proliferation was completely diminished in the presence of Rapa. These results suggest that HB-EGF induced heart fibrosis and proliferation of cardiac fibroblasts occurs through activation of the Akt/mTor/p70s6k pathway.
Type 2 diabetes mellitus (T2DM) is a major risk factor for developing cardiovascular disease and represents a serious public health problem, with high rates of mortality and morbidity worldwide. T2DM etiology is complex and multifactorial and is associated with several complications, including those at myocardium level. Diabetic cardiomyopathy (DCM) is viewed as a specific cardiomyopathy and defined as structural and functional changes in the myocardium due to metabolic and cellular abnormalities induced by diabetes. T2DM has long been classified as an inflammatory disease and recent studies have identified the importance of the inflammatory process in the development and progression of heart failure. In this review, the authors outline the main mechanisms underlying the potential contribution of the inflammatory process in the development and evolution of DCM. In addition, potential therapeutic strategies against inflammation of DCM are discussed.
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a research tool to study the process of adipocyte differentiation. Treatment of various preadipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. However, the molecular basis for the adipogenic actions of indomethacin had remained unclear. In this report, we show that indomethacin binds and activates peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPAR gamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPAR gamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPAR gamma are also efficacious activators of PPAR alpha, a liver-enriched PPAR subtype that plays a key role in peroxisome proliferation. Interestingly, several NSAIDs have been reported to induce peroxisomal activity in hepatocytes both in vitro and in vivo. Our findings define a novel group of PPAR gamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity.
High-mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. Its expression is increased in diabetic cardiomyopathy (DCM), but its role is unclear. We investigated the potential role and mechanism of HMGB1 in diabetes-induced myocardial fibrosis and dysfunction in mice.
In vivo, type 1 diabetes was induced by streptozotocin (STZ) in mice. HMGB1 expression was knocked down by lentivirus-mediated short-hairpin RNA (shRNA). Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. HMGB1, collagen I and III, and transforming growth factor β1 (TGF-β1) expression was quantified by immunostaining and western bolt analysis. In vitro, isolated neonatal cardiac fibroblasts were treated with high glucose (HG) or recombinant HMGB1 (rHMGB1). Pharmacologic (neutralizing anti-HMGB1 antibody) or genetic (shRNA-HMGB1) inhibition of HMGB1 was used to investigate the role of HMGB1 in HG-induced functional changes of cardiac fibroblasts.
In vivo, HMGB1 was diffusely expressed in the myocardium of diabetic mice. HMGB1 silencing ameliorated left ventricular dysfunction and remodeling and decreased collagen deposition in diabetic mice. In vitro, HG induced HMGB1 translocation and secretion in both viable cardiomyocytes and fibroblasts. Administration of rHMGB1 dose-dependently increased the expression of collagens I and III and TGF-β1 in cardiac fibroblasts. HMGB1 inhibition reduced HG-induced collagen production, matrix metalloproteinase (MMP) activities, proliferation, and activated mitogen-activated protein kinase signaling in cardiac fibroblasts.
HMGB1 inhibition could alleviate cardiac fibrosis and remodeling in diabetic cardiomyopathy. Inhibition of HMGB1 might have therapeutic potential in the treatment of the disease.
-The angiotensin converting enzyme 2 and Ang 1-7/MasR axis is emerging as a key pathway that can modulate the development of diabetic cardiomyopathy. We studied the effects of Ang 1-7 on diabetic cardiomyopathy in db/db diabetic mice to elucidate the therapeutic effects and mechanism of action.
-Ang 1-7 was administered to 5-month old male db/db mice for 28 days via implanted micro-osmotic pumps. Ang 1-7 treatment ameliorated myocardial hypertrophy and fibrosis with normalization of diastolic dysfunction assessed by pressure-volume loop analysis and echocardiography. The functional improvement by Ang 1-7 was accompanied by a reduction in myocardial lipid accumulation and systemic fat mass and inflammation, and increased insulin-stimulated myocardial glucose oxidation. Increased myocardial PKC levels and loss of phosphorylation of Erk1/2 were prevented by Ang 1-7. Furthermore, Ang 1-7 treatment decreased cardiac triacylglycerol and ceramide levels in db/db mice, concomitantly with an increase in myocardial adipose triglyceride lipase (ATGL) expression. Changes in ATGL expression correlated with increased SIRT1 levels and deacetylation of FOXO1.
-We identified a novel beneficial effect of Ang 1-7 on diabetic cardiomyopathy that involved a reduction in cardiac hypertrophy and lipotoxicity, adipose inflammation and an upregulation of ATGL. Ang 1-7 completely rescued the diastolic dysfunction in the db/db model. Ang 1-7 represents a promising therapy for diabetic cardiomyopathy associated with type 2 diabetes.
Diabetic encephalopathy is characterised by cognitive impairment, neurochemical and structural abnormalities. The aim of the study was to investigate the effects of ibuprofen on diabetic encephalopathy and potential mechanisms.
Diabetes was induced through a single intraperitoneal injection of streptozotocin (60mg/kg). Diabetic rats were treated with ibuprofen (40mg/kg) by gavage for 8weeks. Cognitive performances were evaluated using Morris water maze. The temporal cortex and hippocampus were obtained to evaluate the levels of advanced glycation endproducts (AGEs) and their receptor (RAGE), the activity, protein expression, and mRNA levels of -amyloid precursor protein cleaving enzyme 1 (BACE1), the protein and mRNA expression of peroxisome proliferator-activated receptor (PPAR ), and the protein expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Blood was obtained for the evaluation of interleukin 1 level.
Chronic ibuprofen treatment significantly prevented the decline in learning and memory ability of diabetic rats and loss of neurons in the CA1 and CA3 areas of the hippocampus. Moreover, ibuprofen treatment markedly reduced the activity, protein, and mRNA levels of BACE1, AGEs level, protein expression of RAGE, COX-2, and iNOS in brain, and interleukin 1 level in serum, while increasing the protein and mRNA expression of PPAR in the brain of diabetic rats. However, ibuprofen had no effects on the hyperglycaemia and the body weight of diabetic rats.
These findings demonstrated that ibuprofen markedly ameliorated diabetic encephalopathy, potentially reflecting the down-regulation of BACE1, the suppression of the AGEs/RAGE axis, and anti-inflammation in diabetic rat brain.
Telmisartan is an angiotensin II receptor blocker, which acts as a partial agonist of peroxisome proliferator activator receptor-γ (PPAR-γ). Because PPAR-γ initiates a variety of antiinflammatory responses, the effect on myocardial ischemia is to be elucidated.
The left anterior descending arteries were ligated to induce myocardial infarction in rats. The animals were assigned to 4 groups: (1) control (saline, n = 6), (2) telmisartan (10 mg·kg·d, n = 6), (3) telmisartan + GW9662 (PPAR-γ-antagonist) (10 mg·kg·d of telmisartan and 1 mg·kg·d of GW9662, n = 6), and (4) amlodipine (10 mg·kg·d, n = 8) groups. Telmisartan reduced mean blood pressure compared with that in the control group. There was no statistical difference among the telmisartan, telmisartan + GW9662 and amlodipine groups. The end-diastolic left ventricular diameter was smaller in telmisartan group compared with that in the control group; GW9662 negated the effect of telmisartan. The thickness of the ventricular septum was kept in the telmisartan group compared with that in the control group; GW9662 negated the effect. Histopathologic analyses showed that telmisartan suppressed myocardial fibrosis compared with that of the control, whereas GW9662 negated the telmisartan effect.
Telmisartan suppresses pathological remodeling by PPAR-γ agonistic activities independent of its antihypertensive effects.