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Noscapine has been mentioned as one of the effective drugs with potential therapeutic applications. With few side effects and amazing capabilities, noscapine can be considered different from other opioids‐like structure compounds. Since 1930, extensive studies have been conducted in the field of pharmacological treatments from against malaria to control cough and cancer treatment. Furthermore, recent studies have shown that noscapine and some analogues, like 9‐bromonoscapine, amino noscapine, and 9‐nitronoscapine, can be used to treat polycystic ovaries syndrome, stroke, and other diseases. Given the numerous results presented in this field and the role of different receptors in the therapeutic effects of noscapine, we aimed to review the properties, therapeutic effects, and the role of receptors in the treatment of noscapine. [ABSTRACT FROM AUTHOR]

Abstract Objective The goal of this study was to explore the role of bradykinins and bradykinin 1 receptor (B1R) in murine lupus nephritis. Methods C57BL/6 and MRL/lpr mice were compared for renal expression of B1R and B2R by western blot and immunohistochemistry. MRL/lpr lupus-prone mice were administered the B1R antagonist, SSR240612 for 12 weeks, and monitored for blood pressure, proteinuria, renal function, and serum autoantibodies. Results Renal B1R:B2R ratios were significantly upregulated in MRL/lpr mice compared with B6 controls. B1R blockade ameliorated renal pathology lesions, proteinuria, and blood pressure, accompanied by lower serum IgG and anti-dsDNA autoantibody levels, reduced splenic marginal zone B cells and CD4+ T cells, and renal infiltrating CD4+ T cells, macrophages, and neutrophils. Both urine and renal CCL2 and CCL5 chemokines were also decreased in the B1R blocked MRL/lpr mice. Conclusion Bradykinin receptor B1R blockade ameliorates both systemic immunity and renal inflammation possibly by inhibiting multiple chemokines and renal immune cell infiltration. B1R blockade may be particularly attractive in subjects with concomitant lupus nephritis and hypertension.

The Kallikrein–Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p

The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p < 0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies. [ABSTRACT FROM AUTHOR]

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Abstract: An assay to quantify several possible breast cancer peptide biomarkers in human serum has been developed and validated, using liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). The peptides include bradykinin, Hyp3-bradykinin, des-Arg9-bradykinin and fragments of fibrinogen α-chain (Fib-α[605–629]), inter-α-trypsin inhibitor heavy chain 4 (ITIH4[666–687]) and complement component 4a (C4a[1337–1350]). Ile13-ITIH4[666–687], d20-C4a[1337–1350] and Sar-D-Phe8-des-Arg9-bradykinin were used as internal standards. Bovine plasma, with 2mM captopril and 2mM d-l-mercaptoethanol-3-guanidino-ethylthiopropanoic acid (MEGETPA) to prevent rapid degradation of the bradykinins, was used as analyte-free matrix. Recoveries for solid-phase extraction (SPE) on mixed-mode weak cation exchange sorbents were between 62 and 90%. Multiple reaction monitoring (MRM) on a triple quadrupole mass spectrometer equipped with a heated electrospray source (H-ESI), operating in the positive ion-mode, was used for detection. The assay was fully validated and stabilities of the peptides were extensively explored. Bradykinin (10–500ng/ml), Hyp3-bradykinin (4–200ng/ml), des-Arg9-bradykinin (2–100ng/ml), Fib-α[605–629] (120–3000ng/ml), ITIH4[666–687] (0.4–10ng/ml) and C4a[1337–1350] (1–25ng/ml) were simultaneously quantified with deviations from the nominal concentrations below 22% and intra- and inter-assay precisions below 15 and 20%, respectively, for all peptides at all concentrations. The method has been successfully applied to several serum samples from breast cancer patients and matched controls. [Copyright &y& Elsevier]

Abstract: Separating closely related peptides (those differing by one or two amino acids or the chirality of a single amino acid) can be challenging using reversed-phase liquid chromatography (LC), ion-exchange LC, or using ion-pairing agents. Also, the mobile phases that give the best separations in these modes may not be electrospray ionization mass spectrometry (ESI-MS) compatible. Forty-two peptides from 11 peptide families were separated on three macrocyclic glycopeptide stationary phases in reverse-phase mode using ESI-MS-compatible mobile phases. The peptide classes studied were angiotensin, bradykinin, α-bag cell factor, β,γ-bag cell factor, β-casomorphin, dynorphin, enkephalin, leucokinin, lutinizing hormone releasing hormone, neurotinsin, substance P, and vasopressin. High selectivity was observed for single amino acid substitutions (achiral and chiral) regardless of the position of the substitution in the sequence. Mobile phase optimization, its effect on peptide elution behavior, and chromatographic efficiency is also discussed. Using LC–ESI-MS, a 2ng limit of detection was obtained, two orders of magnitude lower than the UV detection limit. [Copyright &y& Elsevier]

The effects of the specific angiotensin II (Ang II) AT1receptor blocker valsartan on events related to restenosis were investigated in rabbits after common carotid balloon injury. Six animals were given valsartan from two days prior to injury until 14 days post-injury. Three control groups (n=6 in each group) were either sham-operated, untreated or treated with the angiotensin-converting enzyme (ACE) inhibitor, captopril. Both ACE inhibition and AT1-receptor blockade had marked effects on plasma levels of endothelin ET1, thromboxane TXB2 and 6-keto-PGF1-alpha. The most dramatic effects on ET1 levels were seen in rabbits treated with valsartan, where levels were reduced to values close to those for sham-operated animals (96.85 vs. 86.45 pg/ml). Captopril treatment led to a statistically significant (p<0.01) reduction in ET1 levels compared with untreated animals, but the reduction was only about half that seen with AT1receptor blockade. TXB2 levels doubled (202.58 vs. 413.28 pg/ml) upon arterial injury in control animals but rose by only 20—35% in rabbits treated with captopril (246.45 pg/ml) or valsartan (268.13). In untreated animals, 6-keto-PGF1-alpha levels decreased slightly after injury, but for both the captopril and valsartan groups, there were significant increases in levels of this prostaglandin derivative, effects attributed to the action of bradykinins. Levels were highest in the captopril-treated animals. Valsartan and captopril treatment led to a significant reduction in neointimal thickness and the extent of lumen stenosis compared with untreated animals. Both treatments were effective in reducing neointimal area and significantly (p<0.05) reduced cell proliferation. The differences between treatments can be attributed to the different actions of the agents, as valsartan leaves the AT2-receptor unblocked, while captopril, through inhibition of Ang II synthesis, prevents stimulation of both receptors. A combination of both treatments may be a possible way forward in the clinical prevention of restenosis. [ABSTRACT FROM PUBLISHER]

The mucosal plasma exudate with its proteins, enzymes, derived peptides, and matrix molecules is an important factor in inflammatory airway diseases. This study investigated whether topical glucocorticosteroid treatment influences mucosal exudation of bulk plasma (fibrinogen) and the generation of plasma-derived mediators (bradykinins) in seasonal allergic rhinitis. Twenty-two patients with birch-pollen-induced allergic rhinitis participated in a double-blind, randomized, placebo-controlled study during the birch pollen season in 1989. After a 2-week run-in period, the participants received treatment with budesonide (200 micrograms per nasal cavity and day) or placebo. The patients kept a diary to record their daily nasal symptoms (itching, sneezing, nasal blockage, and secretion). The amount of birch pollen in the air was determined with the aid of a Burkhard pollen trap. A nasal lavage was performed once a week, and the levels of bradykinins and fibrinogen were determined in the lavage fluid samples. The birch pollen season was very mild, resulting in only minor nasal symptoms. In spite of the low pollen exposure, treatment with budesonide reduced the lavage fluid levels of both bradykinins and fibrinogen. The present results show that topical glucocorticosteroid treatment attenuates plasma exudation and the generation of plasma-derived mediators in seasonal allergic rhinitis. This action may not result from simple vascular antipermeability effects of the drug but may rather reflect the anti-inflammatory efficacy of topical glucocorticoids in the airway mucosa. [ABSTRACT FROM AUTHOR]

Experimental data suggest the possibility that common bronchodilators, such as the xanthines and β-adrenoceptor agonists, may produce microvascular anti-permeability effects in the subepithelial microcirculation of the airways. In this study, we have examined the effect of bronchodilators given intravenously on exudation of differentsized plasma proteins (albumin and fibrinogen) and the generation of plasma-derived peptides (bradykinins) in human nasal airways challenged with histamine. In a double-blind, crossover, placebo-controlled and randomised trial, 12 normal volunteers were given IV infusions of terbutaline sulphate, theophylline and enprofylline to produce therapeutic drug levels. The effect of topical nasal provocation with histamine was closely followed by frequently nasal lavage with saline. The lavage fluid levels of albumin, fibrinogen and bradykinins increased significantly after each histamine provocation. The ratio of albumin-to-fibrinogen in plasma and the lavage fluid was 24 and 56, respectively, indicating that topical histamine provocation induced a largely non-sieved flux of macromolecules across the endothelial-epithelial barriers. The systemically administered drugs did not affect the nasal symptoms (sneezing, secretion and blockage), nor did they significantly reduce the levels of plasma proteins and plasma-derived mediators in the nasal lavage fluids. The present data suggest that systemic xanthines and β-adrenoceptor agonists, at clinically employed plasma levels, may not affect the microvascular (and epithelial) exudative permeability and the bradykinin forming capacity of human airways. [ABSTRACT FROM AUTHOR]

COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches. [ABSTRACT FROM AUTHOR]