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Objective: We aimed to broaden our understanding of a potential interaction between B1R and TLR4, considering earlier studies suggesting that lipopolysaccharide (LPS) may trigger B1R stimulation. Methods: We assessed the impact of DBK and LPS on the membrane potential of thoracic aortas from C57BL/6, B1R, or TLR4 knockout mice. Additionally, we examined the staining patterns of these receptors in the thoracic aortas of C57BL/6 and in endothelial cells (HBMEC). Results: DBK does not affect the resting membrane potential of aortic rings in C57BL/6 mice, but it hyperpolarizes preparations in B1KO and TLR4KO mice. The hyperpolarization mechanism in B1KO mice involves B2R, and the TLR4KO response is independent of cytoplasmic calcium influx but relies on potassium channels. Conversely, LPS hyperpolarizes thoracic aorta rings in both C57BL/6 and B1KO mice, with the response unaffected by a B1R antagonist. Interestingly, the absence of B1R alters the LPS response to potassium channels. These activities are independent of nitric oxide synthase (NOS). While exposure to DBK and LPS does not alter B1R and TLR4 mRNA expression, treatment with these agonists increases B1R staining in endothelial cells of thoracic aortic rings and modifies the staining pattern of B1R and TLR4 in endothelial cells. Proximity ligation assay suggests a interaction between the receptors. Conclusion: Our findings provide additional support for a putative connection between B1R and TLR4 signaling. Given the involvement of these receptors and their agonists in inflammation, it suggests that drugs and therapies targeting their effects could be promising therapeutic avenues worth exploring. [ABSTRACT FROM AUTHOR]

The present study investigates the distribution and dynamics of gonadotropin-releasing hormone I (GnRH I) and bradykinin in the air-breathing catfish, Heteropneustes fossilis, in relation to the reproductive cycle. Changes in bradykinin, bradykinin B2-receptor, and ovarian GnRH I regulation were demonstrated during the reproductive cycle. The localization of GnRH I, bradykinin, and their respective receptors in the ovaries was investigated by immunohistochemistry, while their levels were quantified by slot/western blot followed by densitometry. GnRH I and its receptor were mainly localized in the cytoplasm of oocytes during the early previtellogenic phase. However, as the follicles grew larger, immunoreactivity was observed in the granulosa and theca cells of the late previtellogenic follicles. The ovaries showed significantly higher expression of GnRH I protein and its receptor during the early to mid-previtellogenic phase, suggesting their involvement in follicular development. Bradykinin and bradykinin B 2 -receptor showed a distribution pattern similar to that of GnRH I and its receptor. This study further suggested the possibility that bradykinin regulates GnRH I synthesis in the ovary. Thus, we show that the catfish ovary has a GnRH-bradykinin system and plays a role in follicular development and oocyte maturation in H. fossilis. • Catfish, Heteropneustes fossilis ovary possess GnRH I and bradykinin system. • GnRH I and bradykinin and their receptors are present in the same cell types during different phase of reproductive cycle. • GnRH I, bradykinin and their receptors were highest during previtellogenic phase which decreased in later phases. • We hypothesized bradykinin may act as a regulator of GnRH in the ovaries of H. fossilis. [ABSTRACT FROM AUTHOR]

Bradykinin B1 receptor (B1R) has garnered attention as a cancer therapeutic and diagnostic target. Several reports on radiolabelled derivatives of B1R antagonists have shown favourable properties as imaging agents in cells highly expressing hB1R following transfection. In the present study, we assessed whether radiolabelled probes can detect B1R endogenously expressed in cancer cells. To this end, we evaluated 111In-labelled derivatives of a B1R antagonist ([111In]In-DOTA-Ahx-R954) using glioblastoma cell lines (U87MG and U251MG) with different B1R expression levels. Cellular uptake studies showed that the specific accumulation of [111In]In-DOTA-Ahx-R954 in U87MG was higher than that in U251MG, which correlated with B1R expression levels. Tissue distribution in U87MG-bearing mice revealed approximately 2-fold higher radioactivity in tumours than in the muscle in the contralateral leg. The specific accumulation of [111In]In-DOTA-Ahx-R954 in the tumour was demonstrated by the reduction in the tumour-to-plasma ratios in nonlabelled R954-treated mice. Moreover, ex vivo autoradiographic images revealed that the intratumoural distribution of [111In]In-DOTA-Ahx-R954 correlated with the localisation of B1R-expressing glioblastoma cells. In conclusion, we demonstrated that [111In]In-DOTA-Ahx-R954 radioactivity correlated with B1R expression in glioblastoma cells, indicating that radiolabelled derivatives of the B1R antagonist could serve as promising tools for elucidating the involvement of B1R in cancer. [ABSTRACT FROM AUTHOR]

Proteins from different species have been docked with aflatoxin B1 (AFB1) and identified 3 proteins (prostaglandin-E(2)9-reductase from Oryctolagus uniculus, proto-oncogene serine/threonine-protein kinase Pim-1 and human immunoglobulin G (hIgG)) as potential candidates to develop an electrochemical sensor. Fluorescence spectroscopy experiments have confirmed the interaction of hIgG with AFB1 with an affinity constant of 4.6 × 105 M−1. As a proof-of-concept, hIgG was immobilized on carbon nanocomposite (carbon nanotube-nanofiber, CNT-F)-coated glassy carbon electrode (GCE). FT-IR spectra, HR-TEM and BCA assay have confirmed successful immobilization of hIgG on the electrode (hIgG@CNT-F/GCE). The preparation of this protein electrochemical sensor requires only 1 h 36 min, which is fast as compared with preparing an electro immunosensor. hIgG@CNT-F/GCE has displayed an excellent AFB1 limit of detection (0.1 ng/mL), commendable selectivity in the presence of two other mycotoxins (ochratoxin A and patulin) and the detection of AFB1 in spiked peanuts and corn samples. [ABSTRACT FROM AUTHOR]

Background and Purpose: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein‐kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown. Experimental Approach: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod‐induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention. Key Results: Expression of Factor XII was markedly up‐regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod‐induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil‐vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation. Conclusion and Implications: Activation of Factor XII promoted psoriasis via prekallikrein‐dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis. [ABSTRACT FROM AUTHOR]

GABA (γ–amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well–known GABAB1 inhibitors and pharmaceutically important drugs. However, there is a huge demand for more chiral GABA aryl analogues with promising pharmacological actions. Here, we demonstrate the chiral ligand acetyl–protected amino quinoline (APAQ) mediated enantioselective synthesis of GABAB1 inhibitor drug scaffolds from easily accessible GABA via Pd–catalyzed C(sp3)−H activation. The synthetic methodology shows moderate to good yields, up to 74% of ee. We have successfully demonstrated the deprotection and removal of the directing group to synthesize R–tolibut in 86% yield. Further, we employed computation to probe the binding of R–GABA analogues to the extracellular domain of the human GABAB1 receptor. Our Rosetta–based molecular docking calculations show better binding for four R–enantiomers of GABA analogues than R–baclofen and R–phenibut. In addition, we employed GROMACS MD simulations and MMPB(GB)SA calculations to identify per–residue contribution to binding free energy. Our computational results suggest analogues (3R)‐4‐amino‐3‐(3,4‐dimethylphenyl) butanoic acid, (3R)‐4‐amino‐3‐(3‐fluorophenyl) butanoic acid, (3R)‐3‐(4‐acetylphenyl)‐4‐aminobutanoic acid, (3R)‐4‐amino‐3‐(4‐methoxyphenyl) butanoic acid, and (3R)‐4‐amino‐3‐phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here. [ABSTRACT FROM AUTHOR]

Peritoneal B cells can be divided into B1 cells (CD11b+CD19+) and B2 cells (CD11b-CD19+) based on CD11b expression. B1 cells play a crucial role in the innate immune response by producing natural antibodies and cytokines. B2 cells share similar traits with B1 cells, influenced by the peritoneal environment. However, the response of both B1 and B2 cells to the same stimuli in the peritoneum remains uncertain. We isolated peritoneal B1 and B2 cells from mice and assessed differences in Interleukin-10(IL-10) secretion, apoptosis, and surface molecule expression following exposure to LPS and Interleukin-21(IL-21). Our findings indicate that B1 cells are potent IL-10 producers, possessing surface molecules with an IgMhiCD43+CD21low profile, and exhibit a propensity for apoptosis in vitro. Conversely, B2 cells exhibit lower IL-10 production and surface markers characterized as IgMlowCD43-CD21hi, indicative of some resistance to apoptosis. LPS stimulates MAPK phosphorylation in B1 and B2 cells, causing IL-10 production. Furthermore, LPS inhibits peritoneal B2 cell apoptosis by enhancing Bcl-xL expression. Conversely, IL-21 has no impact on IL-10 production in these cells. Nevertheless, impeding STAT3 phosphorylation permits IL-21 to increase IL-10 production in peritoneal B cells. Moreover, IL-21 significantly raises apoptosis levels in these cells, a process independent of STAT3 phosphorylation and possibly linked to reduced Bcl-xL expression. This study elucidates the distinct functional and response profiles of B1 and B2 cells in the peritoneum to stimuli like LPS and IL-21, highlighting their differential roles in immunological responses and B cell diversity. • Peritoneal B1 cells (IgMhiCD43+CD21lo) are potent IL-10 producers and prone to apoptosis in vitro. • Peritoneal B2 cells (IgMloCD43-CD21hi) show lower IL-10 production and apoptosis resistance than B1 cells. • LPS enhances IL-10 production and inhibits apoptosis via MAPK and Bcl-xL in B1 and B2 cells. • IL-21 increases apoptosis in peritoneal B cells, possibly due to reduced Bcl-xL, not STAT3. [ABSTRACT FROM AUTHOR]

Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like Urtica dioica (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation. [ABSTRACT FROM AUTHOR]

This review contains the results of Polish (Central Europe) ethnomedical studies that describe the treatment of urinary tract diseases with wild and cultivated plants. The study includes only the plants that are used to treat the urinary tract, excluding prostate diseases. A review of the literature was carried out to verify the pharmacological use of the plants mentioned in the interviews. Based on this, the study reviews the pharmacological activities of all the recorded species and indicates their most important chemical compounds. Fifty-three species (belonging to 30 families) were selected for the study. The Compositae (eight species), Rosaceae (six species), and Apiaceae (six species) are the most common families used in the treatment of urinary diseases in Polish folk medicine. Both in vitro and in vivo studies have confirmed that many of these plant species have beneficial properties, such as diuretic, antihyperuricemic, antimicrobial, and anti-inflammatory activity, or the prevention of urinary stone formation. These effects are exerted through different mechanisms, for example, through the activation of bradykinin B2 receptors, inhibition of xanthine oxidase, or inhibition of Na+-K+ pump. Many plants used in folk medicine are rich in phytochemicals with proven effectiveness against urinary tract diseases, such as rutin, arbutin, or triterpene saponins. [ABSTRACT FROM AUTHOR]

The article focuses on hereditary angioedema, a rare disorder characterized by recurrent episodes of mucosal swelling due to increased vascular permeability. It discusses the genetic basis of the disease, typically caused by mutations in the SERPING1 gene. Management strategies include prophylactic treatments like bradykinin receptor inhibitors, Cl inhibitor replacement therapies, and kallikrein inhibitors, which aim to prevent or mitigate acute attacks triggered by various factors.

A series of novel 4-Hydroxyquinazoline derivatives were designed and synthesized to enhance sensitivity in primary PARPi-resistant cells. Among them, the compound B1 has been found to have superior cytotoxicity in primary PARPi-resistant HCT-15 and HCC1937 cell lines, and dose-dependently suppressed the intracellular PAR formation and enhanced the γH2AX aggregation. Mechanistic study showed that B1 stimulated the formation of intracellular ROS and the depolarization of the mitochondrial membrane, which could increase apoptosis and cytotoxicity. An in vivo study showed that B1 significantly suppressed tumor growth at a dose of 25 mg/kg, and an acute toxicity study confirmed its safety. Molecular docking and dynamics simulations revealed that hydrogen bonding between B1 and ASP766 may be helpful to enhance anti-drug resistance ability. This study suggests that B1 is a potent PARP inhibitor that can overcome PARPi resistance and deserves further investigation. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) seriously threatens human health. High mobility group protein B1 (HMGB1) and M2‐like macrophages are closely associated with core events about human cancers, such as invasion, and metastasis, and cancer microenvironment. This study mainly determined the regulatory effect of HMGB1 in GC cell‐derived exosomes on M2‐like macrophage polarization as well as the underlying mechanism. HMGB1 was found to be highly expressed in gastric tissue specimens, which might lead to the poor prognosis of GC. High levels of HMGB1 were also observed in the plasma of GC patients, indicating the possibility that it regulates the immune microenvironment via exosomes. Further study revealed and confirmed the regulatory effect of exosomes derived from GC cells with high HMGB1 level on inducing M2‐like macrophage polarization. Mechanistically, by interacting with the transcription factor POU2F1, exosomal HMGB1 inhibited the transcriptional activity of p50, resulting in the inactivation of NF‐κB signaling pathway and thereby inducing M2‐like macrophage polarization. Moreover, instead of promoting the proliferation of GC cells, exosomes with high HMGB1 levels induced M2‐like macrophage polarization and promoted GC progression. This study reveals a novel mechanism by which HMGB1 promotes GC progression, which may provide new insights for improving the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid type‐1 (TRPV1) channels play key roles in chronic pain conditions and are modulated by different inflammatory mediators to elicit heat sensitisation. Bradykinin is a 9‐amino acid peptide chain that promotes inflammation. The aim of present study is to investigate how bradykinin and prostaglandin receptors (EP3 and EP4) modulate the sensitisation of TRPV1‐mediated responses. Calcium imaging studies of rat dorsal root ganglion (DRG) neurons were employed to investigate the desensitizing responses of TRPV1 ion channels by capsaicin, and the re‐sensitization of TRPV1 by bradykinin, then to explore the role EP3 and EP4 receptors in mediating these bradykinin‐dependent effects. Immunocytochemistry was used to study the co‐expression and distribution of EP4, TRPV1, COX‐1 and B2 in rat DRG neurons. Desensitization was seen upon repeated capsaicin application, we show that bradykinin‐mediated sensitization of capsaicin‐evoked calcium responses in rat DRG neurons occurs is dependent on COX‐1 activity and utilizes a pathway that involves EP4 but not EP3 receptors. Immunocytochemical techniques revealed that EP4, TRPV1, COX‐1 and B2 proteins are expressed mainly in small diameter (<1000 μm2) cell bodies of rat DRG neurons which are typically nociceptors. The present study provides suggestive evidence for a potential signalling pathway through which bradykinin may regulate TRPV1 ion channel function via EP4 receptors. In addition to confirming existing knowledge, the anatomical distribution and colocalization of these proteins in DRG neurons as revealed by this study offer valuable insight. [ABSTRACT FROM AUTHOR]

The most common oral and maxillofacial procedure is surgical removal of impacted third molars, which often results in post-operative inflammatory changes. Many pharmacological and nonpharmacological measures have been tried, to help resolve the same with minimum side effects to patients. Non pharmacological measures are surgery, cryotherapy amongst many others. Pharmacological measures include enzymatic or non-enzymatic preparations like antibiotics, steroids and various analgesic drugs. One such newer preparation is that of bromelain, which is an extract from the pineapple stem and plant. It is rich in thiol endopeptidases, cellulose, glycoproteins and carbohydrates. Bromelain has been very commonly used in a lot of medical interventions like sinusitis, thrombophlebitis, surgical trauma, pyelonephritis, angina pectoris, bronchitis as well as for enhancing absorption. It's direct effect on bradykinin receptors has been affiliated to its analgesic property though it can also be due to its anti-inflammatory action. Research has shown that swelling, time required for healing, pain, bruising is reduced due to its property to digest fibrin; enabling reduced oedema post-operatively. Various dosages of the drug have been used to verify its efficacy but there is no consensus on exact optimum dosages. Hence in this study we aim at determining optimum dosage for bromelain providing an ideal maximum effect to reduce inflammation after removal of impacted third molars. [ABSTRACT FROM AUTHOR]

Microcirculatory and coagulation disturbances commonly occur as pathological manifestations of systemic viral infections. Research exploring the role of the kallikrein–kinin system (KKS) in flavivirus infections has recently linked microvascular dysfunctions to bradykinin (BK)-induced signaling of B2R, a G protein-coupled receptor (GPCR) constitutively expressed by endothelial cells. The relevance of KKS activation as an innate response to viral infections has gained increasing attention, particularly after the reports regarding thrombogenic events during COVID-19. BK receptor (B2R and B1R) signal transduction results in vascular permeability, edema formation, angiogenesis, and pain. Recent findings unveiling the role of KKS in viral pathogenesis include evidence of increased activation of KKS with elevated levels of BK and its metabolites in both intravascular and tissue milieu, as well as reports demonstrating that virus replication stimulates BKR expression. In this review, we will discuss the mechanisms triggered by virus replication and by virus-induced inflammatory responses that may stimulate KKS. We also explore how KKS activation and BK signaling may impact virus pathogenesis and further discuss the potential therapeutic application of BKR antagonists in the treatment of hemorrhagic and respiratory diseases. [ABSTRACT FROM AUTHOR]

The kallikrein–kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected. [ABSTRACT FROM AUTHOR]

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether bradykinin receptor expression and function are conserved across species has not been studied in depth. In this study, we used human DRG tissue from organ donors to provide a detailed characterization of bradykinin receptor expression and bradykinin-induced changes in the excitability of human sensory neurons. We found that B2 and, to a lesser extent, B1 receptors are expressed by human DRG neurons and satellite glial cells. B2 receptors were enriched in the nociceptor subpopulation. Using patch-clamp electrophysiology, we found that acute bradykinin increases the excitability of human sensory neurons, whereas prolonged exposure to bradykinin decreases neuronal excitability in a subpopulation of human DRG neurons. Finally, our analyses suggest that donor's history of chronic pain and age may be predictors of higher B1 receptor expression in human DRG neurons. Together, these results indicate that acute bradykinin-induced hyperexcitability, first identified in rodents, is conserved in humans and provide further evidence supporting bradykinin signaling as a potential therapeutic target for treating pain in humans. [ABSTRACT FROM AUTHOR]

As the most prevalent mycotoxin in agricultural products, aflatoxin B1 not only causes significant economic losses but also poses a substantial threat to human and animal health. AFB1 has been shown to increase the risk of hepatocellular carcinoma (HCC) but the underlying mechanism is not thoroughly researched. Here, we explored the toxicity mechanism of AFB1 on human hepatocytes following low-dose exposure based on transcriptomics and lipidomics. Apoptosis-related pathways were significantly upregulated after AFB1 exposure in all three hES-Hep, HepaRG, and HepG2 hepatogenic cell lines. By conducting a comparative analysis with the TCGA-LIHC database, four biomarkers (MTCH1, PPM1D, TP53I3, and UBC) shared by AFB1 and HCC were identified (hazard ratio > 1), which can be used to monitor the degree of AFB1-induced hepatotoxicity. Simultaneously, AFB1 induced abnormal metabolism of glycerolipids, sphingolipids, and glycerophospholipids in HepG2 cells (FDR < 0.05, impact > 0.1). Furthermore, combined analysis revealed strong regulatory effects between PIK3R1 and sphingolipids (correlation coefficient > 0.9), suggesting potential mediation by the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (AKT) signaling pathway within mitochondria. This study revealed the dysregulation of lipid metabolism induced by AFB1 and found novel target genes associated with AFB-induced HCC development, providing reliable evidence for elucidating the hepatotoxicity of AFB as well as assessing food safety risks. [ABSTRACT FROM AUTHOR]

Moyamoya disease (MMD) is a rare disorder of the cerebrovascular system. It is a steno‐occlusive disease that involves angiogenesis and blood–brain barrier (BBB) disruption. Bradykinin (BK), its metabolite des‐Arg9‐BK, and receptor (B1R) affect angiogenesis and BBB integrity. In this study, we aimed to investigate the changes in BK, B1R and des‐Arg9‐BK levels in the serum and brain tissues of patients with MMD and explore the underlying mechanism of these markers in MMD. We obtained the serum samples and superficial temporal artery (STA) tissue of patients with MMD from the Department of Neurosurgery of the Jining First People's Hospital. First, we measured BK, des‐Arg9‐BK and B1R levels in the serum of patients by means of ELISA. Next, we performed immunofluorescence to determine B1R expression in STA tissues. Finally, we determined the underlying mechanism through Western blot, angiogenesis assay, immunofluorescence, transendothelial electrical resistance and transcytosis assays. Our results demonstrated a significant increase in the BK, des‐Arg9‐BK and B1R levels in the serum of patients with MMD compared to healthy controls. Furthermore, an increase in the B1R expression level was observed in the STA tissues of patients with MMD. BK and des‐Arg9‐BK could promote the migratory and proliferative abilities of bEnd.3 cells and inhibited the formation of bEnd.3 cell tubes. In vitro BBB model showed that BK and des‐Arg9‐BK could reduce claudin‐5, ZO‐1 and occluding expression and BBB disruption. To the best of our knowledge, our results show an increase in BK and B1R levels in the serum and STA tissues of patients with MMD. BK and Des‐Arg9‐BK could inhibit angiogenesis, promote migratory and proliferative capacities of cells, and disrupt BBB integrity. Therefore, regulating BK, des‐Arg9‐BK and B1R levels in the serum and the brain could be potential strategies for treating patients with MMD. [ABSTRACT FROM AUTHOR]

Adenosine monophosphate kinase/liver kinase B1/peroxisome proliferator‐activated receptor‐γ coactivator 1‐α (AMPK/LKB1/PGC1α) pathway has a vital role in regulating age‐related diseases. It controls neurogenesis, cell proliferation, axon outgrowth, and cellular energy homeostasis. AMPK pathway also regulates mitochondrial synthesis. The current study evaluated the effect of chrysin on D‐galactose (D‐gal) induced‐aging, neuron degeneration, mitochondrial dysfunction, oxidative stress, and neuroinflammation in mice. The mice were allocated randomly into four groups (10 each group): Group 1: normal control group, Group 2: D‐gal group, Groups 3 and 4: chrysin (125 and 250 mg/kg, respectively). Groups 2–4 were injected with D‐gal (200 mg/kg/day; s.c) for 8 weeks to induce aging. Groups 3 and 4 were orally gavaged every day concurrent with D‐gal. At the end of experiment, behavioral, brain biochemical and histopathological changes were monitored. Chrysin administration elevated discrimination ratio in object recognition, Y Maze percentage alternation, locomotor activity and brain contents of AMPK, LKB1, PGC1α, NAD (P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO‐1), nerve growth factor (NGF) (neurotrophin‐3; NT‐3), and seretonin as well as reduced brain contents of tumor necrosis factor‐alpha (TNF‐α), nuclear factor kappa B (NF‐κB), advanced glycation end products (AGEs) and glial fibrillary acidic protein (GFAP) compared to D‐gal‐treated mice. Chrysin also alleviated cerebral cortex and white matter neurons degeneration. Chrysin protects against neurodegeneration, improves mitochondrial autophagy and biogenesis as well as activates antioxidant genes expression. In addition, chrysin ameliorates neuroinflammation and stimulates the release of NGF and serotonin neurotransmitter. So, chrysin has a neuroprotective effect in D‐gal induced‐aging in mice. [ABSTRACT FROM AUTHOR]

Simple Summary: The basilar artery is a vital cerebral blood vessel common in most vertebrates and constantly supplies blood to the hindbrain where many vital functions are coordinated. Avian basilar arterial responsiveness to vasoactive substances has been characterized only in chickens. In this artery, the endothelium plays an important role in relaxation, and endothelial dependence may explain the lethality of the highly pathogenic avian influenza virus, which reportedly induces apoptosis in the cerebrovascular endothelium. Our present results in ducks suggest a contrast to the previously reported results in chickens with regard to basilar arterial relaxation: The involvement of endothelial nitric oxide as a relaxing factor appears to be reduced in duck basilar arteries. Our research may help scientists to better understand the resistance to the highly pathogenic avian influenza virus that may be conferred by the cerebrovascular endothelium in ducks. The basilar arterial endothelium mediates blood vessel relaxation partly through the release of nitric oxide (NO). Apoptosis of cerebrovascular endothelial cells is linked to a high mortality rate in chickens infected with the highly pathogenic avian influenza virus, but interestingly, ducks exhibit a greater resistance to this virus. In this study, we examined the responsiveness of duck basilar arteries (BAs) to various vasoactive substances, including 5-hydroxytryptamine (5-HT), histamine (His), angiotensin (Ang) II, noradrenaline (NA), acetylcholine (ACh), and avian bradykinin ornithokinin (OK), aiming to characterize the receptor subtypes involved and the role of endothelial NO in vitro. Our findings suggest that arterial contraction is mediated with 5-HT1 and H1 receptors, while relaxation is induced with β3-adrenergic and M3 receptors. Additionally, OK elicited a biphasic response in duck BAs, and Ang II had no effect. Endothelial NO appears to be crucial in relaxation mediated with M3 and OK receptors but not β3-adrenergic receptors in the duck BA. The reduced endothelial NO involvement in the receptor-mediated relaxation response in duck BAs represents a clear difference from the corresponding response reported in chicken BAs. This physiological difference may explain the differences in lethality between ducks and chickens when vascular endothelial cells are infected with the virus. [ABSTRACT FROM AUTHOR]

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis. [ABSTRACT FROM AUTHOR]

Arsenic contamination in drinking water causes a global public health problem. Emerging evidence suggests that arsenic may act as an environmental risk factor for anxiety disorders. However, the exact mechanism underlying the adverse effects has not been fully elucidated. This study aimed to evaluate the anxiety-like behaviors of mice exposed to arsenic trioxide (As2O3), to observe the neuropathological changes, and to explore the link between the GABAergic system and behavioral manifestations. For this purpose, male C57BL/6 mice were exposed to various doses of As2O3 (0, 0.15, 1.5, and 15 mg/L) through drinking water for 12 weeks. Anxiety-like behaviors were assessed using the open field test (OFT), light/dark choice test, and elevated zero maze (EZM). Neuronal injuries in the cerebral cortex and hippocampus were assessed by light microscopy with H&E and Nissl staining. Ultrastructural alteration in the cerebral cortex was assessed by transmission electron microscope (TEM). The expression levels of GABAergic system-related molecules (i.e., glutamate decarboxylase, GABA transporter, and GABAB receptor subunits) in the prefrontal cortex (PFC) were determined by qRT-PCR and western blotting. Arsenic exposure showed a striking anxiogenic effect on mice, especially in the group exposed to 15 mg/L As2O3. Light microscopy showed neuron necrosis and reduced cell counts. TEM revealed marked ultrastructural changes, including the vacuolated mitochondria, disrupted Nissl bodies, an indentation in the nucleus membrane, and delamination of myelin sheath in the cortex. In addition, As2O3 influenced the GABAergic system in the PFC by decreasing the expression of the glutamate decarboxylase 1 (GAD1) and the GABAB2 receptor subunit, but not the GABAB1 receptor subunit. To sum up, sub-chronic exposure to As2O3 is associated with increased anxiety-like behaviors, which may be mediated by altered GABAergic signaling in the PFC. These findings shed light on the mechanisms responsible for the neurotoxic effects of arsenic and therefore more cautions should be taken. [ABSTRACT FROM AUTHOR]

Bradykinin is a small active peptide and is considered an inflammatory mediator in several pathological conditions. Bradykinin exerts its effects by coupling to its receptors, including bradykinin B1 (B1R) and bradykinin B2. B1R has been implicated in the development of various cancers. Our previous study reported that B1R promoted glioblastoma (GBM) development by supporting the migration and invasion of GBM cells. However, the mechanisms underlying the effects of B1R on tumor-associated macrophages (TAMs) and GBM progression remain unknown. Accordingly, to explore the regulatory effects of B1R overexpression (OE) in GBM on tumor-associated immune cells and tumor progression, we constructed a B1R wild-type plasmid and developed a B1R OE model. The results reveal that B1R OE in GBM promoted the expression of ICAM-1 and VCAM-1—cell adhesion molecules—in GBM. Moreover, B1R OE enhanced GBM cell migration ability and monocyte attachment. B1R also regulated the production of the protumorigenic cytokines and chemokines IL-6, IL-8, CXCL11, and CCL5 in GBM, which contributed to tumor progression. We additionally noted that B1R OE in GBM increased the expression of CD68 in TAMs. Furthermore, B1R OE reduced the level of reactive oxygen species in GBM cells by upregulating heme oxygenase-1, an endogenous antioxidant protein, thereby protecting GBM cells from oxidative stress. Notably, B1R OE upregulated the expression of programmed death-ligand 1 in both GBM cells and macrophages, thus providing resistance against T-cell response. B1R OE in GBM also promoted tumor growth and reduced survival rates in an intracranial xenograft mouse model. These results indicate that B1R expression in GBM promotes TAM activity and modulates GBM progression. Therefore, B1R could be an effective target for therapeutic methods in GBM. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), an effective and broad‐spectrum anthracycline antibiotic, is widely used in the treatment of numerous malignancies. However, dose‐dependent cardiotoxicity limits the clinical application of DOX, and the molecular mechanisms are still unknown. In this study, we used the BK receptor B1/B2 double‐knockout (B1B2‐/‐) mice to observe the role of BK receptor in cardiotoxicity induced by DOX and the underlying mechanisms. DOX induced myocardial injury with increased serum levels of AST, CK, and LDH, upregulated tissue expression of bradykinin B1/B2 receptor, FABP4 and iNOS, and downregulated expression of eNOS. However, these altered releases of myocardial enzyme and the expression level of iNOS were significantly prevented in the B1B2‐/‐ mice. We concluded that the activation of both B1 and B2 receptors of BK were involved in the DOX‐induced acute myocardial injury, possibly mediated through iNOS signaling pathways. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a leading cause of death and disability worldwide. A serious risk of acute ischemic stroke (AIS) arises after the stroke event, due to inflammation and edema formation. Inflammation and edema in the brain are mediated by bradykinin, the formation of which is dependent upon a multi-ligand receptor protein called gC1qR. There are currently no preventive treatments for the secondary damage of AIS produced by inflammation and edema. This review aims to summarize recent research regarding the role of gC1qR in bradykinin formation, its role in inflammation and edema following ischemic injury, and potential therapeutic approaches to preventing post-stroke inflammation and edema formation. [ABSTRACT FROM AUTHOR]

Kidney injury represents a global concern, leading to chronic kidney disease. The organophosphate insecticide malathion (MT) demonstrates environmental disturbance and impairment of different mammalian organs, including kidneys. Likewise, gamma-irradiation (IRR) provokes destructive effects in the kidneys. Rutin is a flavonoid glycoside that exhibits nephro-protective and radio-protective properties. This manuscript focused on investigating the protective response of rutin on MT- and IRR-triggered kidney injury in rats. Rats were randomly divided into eight groups of twelve: G1 (C), control; G2 (Rutin), rutin-treated rats; G3 (IRR), gamma-irradiated rats; G4 (MT), malathion-treated rats; G5 (IRR/MT), gamma-irradiated rats treated with malathion; G6 (IRR/Rutin), gamma-irradiated rats treated with rutin; G7 (MT/Rutin), rats treated with malathion and rutin; and G8 (IRR/MT/Rutin), gamma-irradiated rats treated with malathion and rutin, every day for 30 days. The results demonstrated that rutin treatment regulated the biochemical parameters, the oxidative stress, the antioxidant status, and the inflammatory responses due to the down-regulation of the renal NF-κB p65 protein expression. Moreover, it amended the activity of acetylcholinesterase (AchE), angiotensin ACE I, and ACE II-converting enzymes. Besides, it regulated the iNOS, eNOS, miR-129-3p, miR-200c, and miR-210 gene expressions and bradykinin receptor (B1R and B2R) protein expressions. Histopathological examinations of the kidney tissue confirmed these investigated results. It could be concluded that rutin demonstrated nephro/radioprotection and counteracted the toxicological effects triggered in the kidney tissues of IRR, MT, and IRR/MT intoxicated rats, via regulating miR-129-3p, miR-200c-3p, and miR-210-3p gene expressions, which consequently regulated B2R protein expressions, ACE II activity, and HIF-1α production, respectively. [ABSTRACT FROM AUTHOR]

The cardioprotective mechanisms of bradykinin-(1–9) in myocardial infarction were unclear. We investigated the effect of bradykinin-(1–9) on cardiac function, fibrosis, and autophagy induced by myocardial infarction and identified the mechanisms involved. To investigate the cardioprotective effect of bradykinin-(1–9), various doses of bradykinin-(1–9), its B2 receptor blocker HOE140, or their combination were administered to rats via subcutaneous osmotic minipump implantation before myocardial infarction. After 2 days, myocardial infarction was induced by ligation of the left anterior descending coronary artery. After 2 weeks, echocardiographic measurements and euthanasia were performed. Bradykinin-(1–9) treatment attenuated left ventricular dysfunction, fibrosis, and autophagy in rats with myocardial infarction, which was partially reversed by HOE140 administration. Moreover, the downregulatory effect of bradykinin-(1–9) on autophagy was partially reversed by combination with the PI3K inhibitor LY294002. Thus, bradykinin-(1–9) inhibits myocardial infarction-induced cardiomyocyte autophagy by upregulating the PI3K/Akt pathway. • Bradykinin-(1–9) is a core component of the kallikrein–kinin system, which is released in the heart during ischemia. • Bradykinin-(1–9) protects against cardiac fibrosis and inhibits cardiomyocyte autophagy induced by myocardial infarction. • The cardioprotective action of bradykinin-(1–9) is dependent on the activation of PI3K/Akt signaling. [ABSTRACT FROM AUTHOR]

Objective: Endothelial functions in controlling blood flow in placental circulation are still unclear. The present study compares vascular dilations between placental circulation and other vessels, as well as between normal and preeclampsia placental vessels. Methods: Placental, umbilical, and other vessels (cerebral andmesenteric arteries) were collected from humans, sheep, and rats. Vasodilation was tested by JZ101 and DMT. Q-PCR, Western blot, and Elisa were used for molecular experiments. Results: Endothelium-dependent/derived vasodilators, including acetylcholine, bradykinin, prostacyclin, and histamine, mediated no or minimal dilation in placental circulation, which was different from that in other vessels in sheep and rats. There were lower mRNA expressions of muscarinic receptors, histamine receptors, bradykinin receptor 2, endothelial nitric oxide synthesis (eNOS), and less nitric oxide (NO) in human umbilical vessels when compared with placental vessels. Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. The sGC inhibitor ODQ suppressed the reduced baseline caused by the SNP. The decreased baseline by SNP or Bay41-2272 was higher in placental vessels than in umbilical vessels, suggesting that the role of NO/sGC is more important in the placenta. NO concentrations in preeclampsia placental vessels were lower than those in control, while no significant change was found in umbilical plasma between the two groups. eNOS expression was similar between normal and preeclampsia placental vessels, but phosphorylated eNOS levels were significantly lower in preeclampsia. Following serotonin, SNP or Bay41-2272-mediated dilations were weaker in preeclampsia placental vessels. The decreased amplitude of SNP- or Bay41-2272 at baseline was smaller in preeclampsia. The decreased amplitudes of ODQ + SNP were comparable between the two groups. Despite higher beta sGC expression, sGC activity in the preeclampsia placenta was lower. Conclusion: This study demonstrated that receptor-mediated endotheliumdependent dilation in placental circulation was significantly weaker than other vessels in various species. The results, showed firstly, that exogenous NO played a role in regulating the baseline tone of placental circulation via sGC. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels. [ABSTRACT FROM AUTHOR]

Simple Summary: Ecdysone is an essential factor affecting host immunity, in addition to regulating insect metamorphosis. There are two isoforms of ecdysone receptors (EcR) in silkworm, BmEcR-B1, and BmEcR-A. In this study, BmEcR-B1 was found to be more critical than BmEcR-A in responding to BmNPV infection. Further studies confirmed that BmEcR-B1 played an anti-BmNPV role in the participation of 20E, which was associated with 20E-induced apoptosis. This study provides theoretical support for elucidating the resistant mechanism of silkworm to BmNPV and the control of BmNPV disease in sericulture. Bombyx mori nucleopolyhedrovirus (BmNPV) is a serious threat to sericulture. Nevertheless, no effective control strategy is currently available. The innate immunity of silkworm is critical in the antiviral process. Exploring its molecular mechanism provides theoretical support for the prevention and treatment of BmNPV. Insect hormone receptors play an essential role in regulating host immunity. We found a correlation between Bombyx mori ecdysone receptor B1 (BmEcR-B1) and BmNPV infection, whereas the underlying mechanism remains unclear. In this study, the expression patterns and sequence characteristics of BmEcR-B1 and its isoform, BmEcR-A, were initially analyzed. BmEcR-B1 was found to be more critical than BmEcR-A in silkworm development and responses to BmNPV. Moreover, RNAi and an overexpression in BmN cells showed BmEcR-B1 had antiviral effects in the presence of 20-hydroxyecdysone (20E); Otherwise, it had no antiviral activity. Furthermore, BmEcR-B1 was required for 20E-induced apoptosis, which significantly suppressed virus infection. Finally, feeding 20E had no significant negative impacts on larval growth and the cocoon shell, suggesting the regulation of this pathway has practical value in controlling BmNPV in sericulture. The findings of this study provide important theoretical support for understanding the mechanism of the silkworm innate immune system in response to BmNPV infection. [ABSTRACT FROM AUTHOR]

Endothelial cells play an important role in sensing danger signals and regulating inflammation. Several factors are capable of inducing a proinflammatory response (e.g., LPS, histamine, IFNγ, and bradykinin), and these factors act simultaneously during the natural course of the inflammatory reaction. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) also induces a proinflammatory activation of the endothelial cells. Our aim was to investigate the possible cooperation between MASP-1 and other proinflammatory mediators when they are present in low doses. We used HUVECs and measured Ca2+ mobilization, IL-8, E-selectin, VCAM-1 expression, endothelial permeability, and mRNA levels of specific receptors. LPS pretreatment increased the expression of PAR2, a MASP-1 receptor, and furthermore, MASP-1 and LPS enhanced each other's effects in regulating IL-8, E-selectin, Ca2+ mobilization, and changes in permeability in a variety of ways. Cotreatment of MASP-1 and IFNγ increased the IL-8 expression of HUVECs. MASP-1 induced bradykinin and histamine receptor expression, and consequently, increased Ca2+ mobilization was found. Pretreatment with IFNγ enhanced MASP-1-induced Ca2+ mobilization. Our findings highlight that well-known proinflammatory mediators and MASP-1, even at low effective doses, can strongly synergize to enhance the inflammatory response of endothelial cells. [ABSTRACT FROM AUTHOR]

Introduction: Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B2 receptor blockade prevents intradialytic hypotension. Methods: We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B2 receptor blocker, and placebo during hemodialysis. Icatibant or placebo was infused for 30 min before and during hemodialysis in 11 patients on MHD. Results: Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH. Conclusion: Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH. [ABSTRACT FROM AUTHOR]

An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target. Adipose tissue thermogenesis plays a role in appropriate response to cold exposure through incompletely understood mechanisms. Here the authors report that acute cold exposure increases the serum levels of bradykinin, which induces brown adipose tissue thermogenesis and white adipose tissue browning in male mice. [ABSTRACT FROM AUTHOR]

Pseudoallergy is a hypersensitivity condition not triggered by immunoglobulin E (IgE). These conditions can cause various health problems with symptoms identical to IgE-mediated allergic. The symptoms range from mild such as hives, to severe symptoms, such as anaphylactoid. Several drugs are known to activate mast cells directly through the mas-related G protein-coupled receptor X2 (MRGPRX2). MRGPRX2 is a receptor expressed on mast cells and responsible for their activation without being mediated by IgE. This review focuses on the types and methods of drugs that can induce pseudoallergy through MRGPRX2. The literature was collected with keywords in the form of "pseudo allergy" OR "pseudoallergy" AND "drug" AND "induce" NOT "Herb." From this search, it is known that several drugs belonging to the class of antidepressants, antipsychotics, opioids, muscle relaxants, preservatives, antibiotics, radiograph media, cough suppressants, immune response modifiers, retinoids, and Bradykinin B2 receptor antagonist drugs can induce pseudoallergic reactions through MRGPRX2. In addition, the structure of the drug compound can affect its interaction with MRGPRX2 and the emergence of pseudoallergic reactions. [ABSTRACT FROM AUTHOR]

One particularly harmful mycotoxin, aflatoxin B1 (AFB1), usually triggers liver toxicity and oxidative stress in both humans and other mammals. Luteolin (LUTN), a popular active phytochemical molecule, exhibits a strong antioxidant potential. The purpose of this investigation was to explore the potential molecular mechanism in rats and determine if LUTN exhibits protective benefits against AFB1-induced hepatotoxicity. Random selection was used to determine the four treatment groups, each consisting of 24 rats (n = 6). Physiological saline was administered to group 1 (CONT); group 2 received LUTN for a dosage of 50-mg/kg BW. AFB1 was administered to group 3 for a dosage of 0.75-mg/kg BW, and AFB1 with LUTN was given to group 4 at the same dosages mentioned in the previous groups. Rats intoxicated with AFB1 alterations of hepatic transaminases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), displayed periportal mononuclear cell infiltrations, disorganized lobular architecture, and dispersed necrotic cells in their liver tissues. By reducing serum biochemical levels of the hepatic transaminases ALT and AST brought on by AFB1 exposure, our results demonstrated that LUTN treatment considerably restored liver injury. Through lowering the production of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as by boosting the activity of the antioxidant enzyme catalase (CAT) and superoxide dismutase (SOD), LUTN mitigated the oxidative stress brought on by AFB1. Our findings showed that LUTN significantly reversed the liver damage caused by AFB1. When considered as a whole, LUTN may protect the liver from damage brought on by AFB1 by acting as a potential mitigator and may aid in the creation of cutting-edge therapies to treat liver illnesses in humans and/or animals. [ABSTRACT FROM AUTHOR]

Chagas disease, the parasitic infection caused by Trypanosoma cruzi, afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that T. cruzi may fuel heart parasitism by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated in inflamed tissues. Studies in WT and B1R−/− mice showed that T. cruzi DNA levels (15 days post infection—dpi) were sharply reduced in the transgenic heart. FACS analysis revealed that frequencies of proinflammatory neutrophils and monocytes were diminished in B1R−/− hearts whereas CK-MB activity (60 dpi) was exclusively detected in B1R+/+ sera. Since chronic myocarditis and heart fibrosis (90 dpi) were markedly attenuated in the transgenic mice, we sought to determine whether a pharmacological blockade of the des-Arg9-bradykinin (DABK)/B1R pathway might alleviate chagasic cardiomyopathy. Using C57BL/6 mice acutely infected by a myotropic T. cruzi strain (Colombian), we found that daily treatment (15–60 dpi) with R-954 (B1R antagonist) reduced heart parasitism and blunted cardiac injury. Extending R-954 treatment to the chronic phase (120–160 dpi), we verified that B1R targeting (i) decreased mortality indexes, (ii) mitigated chronic myocarditis, and (iii) ameliorated heart conduction disturbances. Collectively, our study suggests that a pharmacological blockade of the proinflammatory KKS/DABK/B1R pathway is cardioprotective in acute and chronic Chagas disease. [ABSTRACT FROM AUTHOR]

• Genetic analysis by RNAi reveals that collagen I is under tonic repression in fibroblasts. • Bradykinin receptor 2 (BDKRB2), a G-protein couple receptor repress collagen I expression and is a modulator of ECM homeostasis. • BDKRB2 effect is independent of bradykinin and canonical TGFβ-SMAD signalling and is conveyed through ERK1/2 inhibition. • BDKRB2 regulation of collagen I appears relevant in various fibrotic conditions such as Keloids and Idiopathic Pulmonary Fibrosis. Imbalance of collagen I expression results in severe pathologies. Apart from activation by the TGFβ-receptor/Smad pathway, control of collagen I expression remains poorly understood. Here, we used human dermal fibroblasts expressing a mCherry fluorescent protein driven by endogenous COL1A1 promoter to functionally screen the kinome and phosphatome. We identify 8 negative regulators, revealing that collagen is under tonic repression. The cell surface receptor BDKRB2 represses collagen I and other pro-fibrotic genes. Interestingly, it also promotes other basal membrane ECM genes. This function is independent of the natural ligand, bradykinin, and of SMAD2/3 factors, instead requiring constant ERK1/2 repression. TGFβ stimulation induces rapid BDKRB2 transcriptional downregulation. Human fibrotic fibroblasts have reduced BDKRB2 levels and enhancing its expression in keloid fibroblasts represses COL1A1. We propose that tonic signalling by BDKRB2 prevents collagen overproduction in skin fibroblasts. [ABSTRACT FROM AUTHOR]

Biallelic mutations in the gene encoding WFS1 underlie the development of Wolfram syndrome (WS), a rare neurodegenerative disorder with no available cure. We have previously shown that Wfs1 deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key receptors, angiotensin II receptor type 2 (Agtr2) and bradykinin receptor B1 (Bdkrb1), was downregulated both in vitro and in vivo across multiple organs in a rat model of WS. Here, we show that the expression of key RAAS components is also dysregulated in neural tissue from aged WS rats and that these alterations are not normalized by pharmacological treatments (liraglutide (LIR), 7,8-dihydroxyflavone (7,8-DHF) or their combination). We found that the expression of angiotensin II receptor type 1a (Agtr1a), angiotensin II receptor type 1b (Agtr1b), Agtr2 and Bdkrb1 was significantly downregulated in the hippocampus of WS animals that experienced chronic experimental stress. Treatment-naïve WS rats displayed different gene expression patterns, underscoring the effect of prolonged experiment-induced stress. Altogether, we posit that Wfs1 deficiency disturbs RAAS functioning under chronic stressful conditions, thereby exacerbating neurodegeneration in WS. [ABSTRACT FROM AUTHOR]

Vasoactive peptides often serve a multitude of functions aside from their direct effects on vasodynamics. This article will review the existing literature on two vasoactive peptides and their involvement in skin homeostasis: adiponectin and--as the main representative of the kallikrein-kinin system--bradykinin. Adiponectin is the most abundantly expressed adipokine in the human organism, where it is mainly localized in fat depots including subcutaneous adipose tissue, from where adiponectin can exert paracrine effects. The involvement of adiponectin in skin homeostasis is supported by a number of studies reporting the effects of adiponectin in isolated human keratinocytes, sebocytes, fibroblasts, melanocytes, and immune cells. Regarding skin pathology, the potential involvement of adiponectin in psoriasis, atopic dermatitis, scleroderma, keloid, and melanogenesis is discussed in this article. The kallikrein-kinin system is composed of a variety of enzymes and peptides, most of which have been identified to be expressed in the skin. This also includes the expression of bradykinin receptors on most skin cells. Bradykinin is one of the very few hormones that is targeted by treatment in routine clinical use in dermatology--in this case for the treatment of hereditary angioedema. The potential involvement of bradykinin in wound healing, psoriasis, and melanoma is further discussed in this article. This review concludes with a call for additional preclinical and clinical studies to further explore the therapeutic potential of adiponectin supplementation (for psoriasis, atopic dermatitis, wound healing, scleroderma, and keloid) or pharmacological interference with the kallikrein-kinin system (for wound healing, psoriasis, and melanoma). [ABSTRACT FROM AUTHOR]

We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce simulated peripheral artery disease (PAD). We hypothesized that in decerebrate, unanesthetized rats with a ligated femoral artery, hindlimb arterial injection of HOE-140 (100 ng, B2 receptor antagonist) would reduce the pressor response to 30 s of electrically induced 1 Hz hindlimb skeletal muscle contraction, and 30 s of 1 Hz hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). We hypothesized no effect of HOE-140 in sham-operated "freely perfused" rats. In both freely perfused (n = 4) and "ligated" (n = 4) rats, we first confirmed efficacious B2 receptor blockade by demonstrating that HOE-140 injection significantly reduced (P < 0.05) the peak increase in mean arterial pressure (peak DMAP) in response to hindlimb arterial injection of bradykinin. In subsequent experiments, we found that HOE-140 reduced the peak DMAP response to muscle contraction in ligated (n = 14; control: 23 ± 2; HOE-140: 17 ± 2 mmHg; P = 0.03) but not freely perfused rats (n = 7; control: 17 ± 3; HOE-140: 18 ± 4 mmHg; P = 0.65). Furthermore, HOE-140 had no effect on the peak DMAP response to stretch in ligated rats (n = 14; control: 37 ± 4; HOE-140: 32 ± 5 mmHg; P = 0.13) but reduced the integrated area under the blood pressure signal over the final -20 s of the maneuver. The data suggest that B2 receptors contribute to the exaggerated exercise pressor reflex in rats with simulated PAD, and that contribution includes a modest role in the chronic sensitization of the mechanically activated channels/afferents that underlie mechanoreflex activation. [ABSTRACT FROM AUTHOR]

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The Coronavirus disease 2019 (COVID-19) outbreak was declared by the World Health Organization (WHO) in March 2020 to be a pandemic and many drugs used at the beginning proved useless in fighting the infection. Lately, there has been approval of some new generation drugs for the clinical treatment of severe or critical COVID-19 infections. Nevertheless, more drugs are required to reduce the pandemic's impact. Several treatment approaches for COVID-19 were employed since the beginning of the pandemic, such as immunomodulatory, antiviral, anti-inflammatory, antimicrobial agents, and again corticosteroids, angiotensin II receptor blockers, and bradykinin B2 receptor antagonists, but many of them were proven ineffective in targeting the virus. So, the identification of drugs to be used effectively for treatment of COVID-19 is strongly needed. It is aimed in this review to collect the information so far known about the COVID-19 studies and treatments. Moreover, the observations reported in this review about carbazoles as a treatment can signify a potentially useful clinical application; various drugs that can be introduced into the therapeutic equipment to fight COVID-19 or their molecules can be used as the basis for designing new antivirals. [ABSTRACT FROM AUTHOR]

Background: Erectile dysfunction (ED) demonstrates seasonal variation with higher rates in winter, and we hypothesize that endothelial damage in erectile tissue caused by bradykinin receptor B1 (B1R) might be detrimental to this change. Aim: To find out direct correlations between cold stress and ED, through which to further investigate the functional roles of B1R in erectile tissue and to elucidate the therapeutic roles of the B1R antagonist in a cold stress-induced ED rat model. Methods: Cold stress rat models are established through long-term intermittent exposure to low temperature. After their erectile function was assessed, ED rats were treated with the B1R antagonist through intraperitoneal injection. Penile tissues were obtained at the end of the experiment after measurement of intracavernosal pressure/mean arterial pressure (ICP/MAP); the location and distribution of cytokine expression were determined by immunohistochemistry; cytokine levels and NOS and CD31 expression were detected by Western blotting; and collagen fibers and smooth muscles were observed through Masson staining. Outcomes: Cold stress impairs erectile function, and the B1R antagonist protects against it. Results: We observed decreased erection frequency, prolonged erection latency time, decreased ICP/MAP, overexpression of B1R, increased expression of cytokines on cavernous sinus endothelium, and increased levels of collagen fibers/smooth muscles on erectile tissue in response to cold stress. Also, NOS and CD31 expression was downregulated. B1R antagonist treatment shows enhanced erectile function through increased erection frequency, shortened erection latency time, and increased ICP/MAP. Also, it reduces collagen fibers/smooth muscles, TNF-a, TGF-ß1, and IL-6 and upregulates the expression of nNOS and CD31. Clinical Translation: Our findings cast new light on the correlations between cold stress and erectile function and potential new applications of existing B1R antagonist drugs in the field of ED. Strengths and Limitations: Our data support that cold stress impairs erectile function. B1R-mediated, cytokine-induced corpus cavernosum fibrosis and endothelial damage might be the main reason behind it, and B1R inhibition protects against fibrosis and endothelial damage. Other ways of B1R antagonist blocking methods in different types of ED still need to be investigated. Conclusion: Long-term intermittent cold stress impairs erectile function, and B1R-mediated, cytokine-induced corpus cavernosum fibrosis and endothelial damage might be the main reason behind it. B1R inhibition also protects against fibrosis and endothelial damage. Our data support the hypothesis that cold stress impairs erectile function and that B1R blockade ameliorates the symptoms of ED, possibly by reversing fibrosis and endothelial damage in erectile tissue. [ABSTRACT FROM AUTHOR]

SCARB1 belongs to class B of Scavenger receptors (SRs) that are known to be involved in binding and endocytosis of various pathogens. SRs have emerging role in regulating innate immunity and host–pathogen interactions by acting in co-ordination with Toll-like receptors.Query Little is known about the function of SCARB1 in milk-derived mammary epithelial cells (MECs). This study reports the role of SCARB1 in infection and its potential association in TLR4 signaling on bacterial challenge in Goat mammary epithelial cells (GMECs). The novelty in the establishment of MEC culture lies in the method that aims to enhance the viability of the cells with intact characteristics upto a higher passage number. We represent MEC culture to be used as a potential infection model for deeper understanding of animal physiology especially around the mammary gland. On E.coli challenge the expression of SCARB1 was significant in induced GMECs at 6 h. Endoribonuclease-esiRNA based silencing of SCARB1 affects the expression of TLR4 and its pathways i.e. MyD88 and TRIF pathways on infection. Knockdown also affected the endocytosis of E.coli in GMECs demonstrating that E.coli uses SCARB1 function to gain entry in cells. Furthermore, we predict 3 unique protein structures of uncharacterized SCARB1 (Capra hircus) protein. Overall, we highlight SCARB1 as a main participant in host defence and its function in antibacterial advances to check mammary gland infections. 77BMn9mgrsGEVLyNf1hg2w Video Abstract [ABSTRACT FROM AUTHOR]

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) α and γ, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta (Cacna1c) in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has swept the whole world and brought about a public health crisis of unprecedented proportions. To combat the rapid transmission and possible deaths due to the disease, researchers and companies around the world are developing all possible strategies. Due to the advantages of safety, specificity, and fewer adverse effects, polypeptide and peptidomimetic drugs are considered promising strategies. This review comprehensively summarizes and discusses the progress in development of peptide drugs for use in the treatment of COVID-19. Based on the latest results in this field, we divided them into clinically approved drugs, clinical trial drugs, and clinically ineffective drugs, and outlined the molecular targets and mechanisms of action one by one to reveal their feasibility as promising therapeutic agents for COVID-19. Notably, monoclonal antibodies have shown beneficial effects in the early stages of infection, while Paxlovid can significantly reduce hospitalization and mortality among non-vaccinated patients. Among clinical experimental drugs, both the interleukin-1 receptor antagonist anakinra and the bradykinin B2 receptor antagonist icatibant are well tolerated and effective in patients with COVID-19, but long-term trials are needed to confirm the durability of efficacy. [ABSTRACT FROM AUTHOR]