Receive wireless sensor data through IoT gateway using web client based on border gateway protocol.

One of the significant topics in the field of the Internet of Things (IoT) pertains to the interaction and information sharing among people. The utilization of the Border Gateway Protocol (BGP) stack enhances the integration of web protocols and sensor networks, leading to greater accessibility. However, the BGP protocol stack introduces substantial overhead to messages transmitted at each layer, resulting in increased data overhead and energy consumption in networks by several orders of magnitude. This paper proposes a method to reduce the overhead on small and medium-sized packets. In multi-temporal networks utilizing BGP, scheduling and aggregating BGP packets at sensor nodes help achieve specific objectives. Various research methodologies and measures are employed to facilitate this, including request classification, BGP response prioritization within the network, determination of maximum acceptable delay, and overall network management. Synchronization and temporal integration of received messages at sensor nodes are performed, considering the maximum allowable delay for each message and the availability of the destination to process the accumulated messages. The evaluation results of the proposed method demonstrate a significant reduction in energy consumption and network traffic, particularly in monitoring applications within multi-stage networks. The protocol stack used is derived from the BGP standard.

BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia-Reperfusion in the Eyes of Sprague Dawley Rats.

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-ß-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia-reperfusion. It was also observed to counteract retinal thinning after ischemia-reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia-reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops.

Single fibre cytoarchitecture in ventilator-induced diaphragm dysfunction (VIDD) assessed by quantitative morphometry second harmonic generation imaging: Positive effects of BGP-15 chaperone co-inducer and VBP-15 dissociative corticosteroid treatment.

Ventilator-induced diaphragm dysfunction (VIDD) is a common sequela of intensive care unit (ICU) treatment requiring mechanical ventilation (MV) and neuromuscular blockade (NMBA). It is characterised by diaphragm weakness, prolonged respirator weaning and adverse outcomes. Dissociative glucocorticoids (e.g., vamorolone, VBP-15) and chaperone co-inducers (e.g., BGP-15) previously showed positive effects in an ICU-rat model. In limb muscle critical illness myopathy, preferential myosin loss prevails, while myofibrillar protein post-translational modifications are more dominant in VIDD. It is not known whether the marked decline in specific force (force normalised to cross-sectional area) is a pure consequence of altered contractility signaling or whether diaphragm weakness also has a structural correlate through sterical remodeling of myofibrillar cytoarchitecture, how quickly it develops, and to which extent VBP-15 or BGP-15 may specifically recover myofibrillar geometry. To address these questions, we performed label-free multiphoton Second Harmonic Generation (SHG) imaging followed by quantitative morphometry in single diaphragm muscle fibres from healthy rats subjected to five or 10 days of MV + NMBA to simulate ICU treatment without underlying confounding pathology (like sepsis). Rats received daily treatment of either Prednisolone, VBP-15, BGP-15 or none. Myosin-II SHG signal intensities, fibre diameters (FD) as well as the parameters of myofibrillar angular parallelism (cosine angle sum, CAS) and in-register of adjacent myofibrils (Vernier density, VD) were computed from SHG images. ICU treatment caused a decline in FD at day 10 as well as a significant decline in CAS and VD from day 5. Vamorolone effectively recovered FD at day 10, while BGP-15 was more effective at day 5. BGP-15 was more effective than VBP-15 in recovering CAS at day 10 although not to control levels. In-register VD levels were restored at day 10 by both compounds. Our study is the first to provide quantitative insights into VIDD-related myofibrillar remodeling unravelled by SHG imaging, suggesting that both VBP-15 and BGP-15 can effectively ameliorate the structure-related dysfunction in VIDD.

Effect of Selected Crosslinking and Stabilization Methods on the Properties of Porous Chitosan Composites Dedicated for Medical Applications.

Chitosan is one of the most commonly employed natural polymers for biomedical applications. However, in order to obtain stable chitosan biomaterials with appropriate strength properties, it is necessary to subject it to crosslinking or stabilization. Composites based on chitosan and bioglass were prepared using the lyophilization method. In the experimental design, six different methods were used to obtain stable, porous chitosan/bioglass biocomposite materials. This study compared the crosslinking/stabilization of chitosan/bioglass composites with ethanol, thermal dehydration, sodium tripolyphosphate, vanillin, genipin, and sodium ß-glycerophosphate. The physicochemical, mechanical, and biological properties of the obtained materials were compared. The results showed that all the selected crosslinking methods allow the production of stable, non-cytotoxic porous composites of chitosan/bioglass. The composite with genipin stood out with the best of the compared properties, taking into account biological and mechanical characteristics. The composite stabilized with ethanol is distinct in terms of its thermal properties and swelling stability, and it also promotes cell proliferation. Regarding the specific surface area, the highest value exposes the composite stabilized by the thermal dehydration method.

Benzo(ghi)perylene (BgP) a black tattoo ingredient induced skin toxicity via direct and indirect mode of DNA damage under UVA irradiation.

Tattooing is a very common fashion trend across all the ages and gender of the society worldwide. Although skin inflammatory diseases are very frequent among tattoo users because of the active chemical ingredients used in tattoo ink, yet no ingredient-specific toxicity study has been performed. Benzo(ghi)perylene (BgP) is one of the PAHs and an important ingredient of black tattoo ink that shows strong absorption in UVA and UVB radiation of sunlight. Therefore, understanding the hazardous potential of BgP especially under UVA exposure is important for the safety of skin of tattoo users by considering the fact that penetration of UVA is in the dermis region where tattoo ingredients reside. To evaluate the hazardous potential of BgP on human skin under UVA exposure, different experimental tools i.e., in-chemico, in-silico and in-vitro were utilized. Our results illustrated that BgP photosensitized under UVA (1.5 mW/cm2) irradiation shows a degradation pattern till 4 h exposure. Photosensitized BgP reduced significant cell viability (%) at 1 µg/ml concentration. However, the pretreatment of singlet and hydroxyl radical quenchers, restoration of cell viability observed, confirmed the role of type-I and type-II photodynamic reactions in phototoxicity of BgP. Further, intracellular uptake of BgP in HaCaT cells was estimated and confirmed by UHPLC analysis. Molecular docking of BgP with DNA and formation of γ-H2AX foci demonstrated the DNA intercalation and double-stranded DNA damaging potential of BgP. Furthermore, acridine orange and ethidium bromide (AO/EB) dual staining showed apoptotic cell death via photosensitized BgP under UVA irradiation. The above findings suggest that BgP reached the human skin cell and induced dermal toxicity via direct and indirect mode of DNA damage under UVA exposure finally promoting the skin cell death. Thus, BgP-containing tattoo ink may be hazardous and may induce skin damage and diseases, especially in presence of UVA radiation of sunlight. To minimize the risk of skin diseases from synthetic ingredients in tattoo ink, the study highlights the importance of developing eco-friendly and skin-friendly tattoo ingredients by companies.

Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats.

Multi-target drug candidate BGP-15 has shown cardioprotective and antiarrhythmic actions in diseased models. Here, we investigated the effects of BGP-15 on ECG and echocardiographic parameters, heart rate variability (HRV), and arrhythmia incidence in telemetry-implanted rats, under beta-adrenergic stimulation by isoproterenol (ISO). In total, 40 rats were implanted with radiotelemetry transmitters. First, dose escalation studies (40-160 mg/kg BGP-15), ECG parameters, and 24 h HRV parameters were assessed. After, rats were divided into Control, Control+BGP-15, ISO, and ISO+BGP-15 subgroups for 2 weeks. ECG recordings were obtained from conscious rats, arrhythmias and HRV parameters were assessed, and echocardiography was carried out. ISO-BGP-15 interaction was also evaluated on an isolated canine cardiomyocyte model. BGP-15 had no observable effects on the ECG waveforms; however, it decreased heart rate. HRV monitoring showed that BGP-15 increased RMSSD, SD1, and HF% parameters. BGP-15 failed to counteract 1 mg/kg ISO-induced tachycardia, but diminished the ECG of ischemia and suppressed ventricular arrhythmia incidence. Under echocardiography, after low-dose ISO injection, BGP-15 administration lowered HR and atrial velocities, and increased end-diastolic volume and ventricle relaxation, but did not counteract the positive inotropic effects of ISO. Two weeks of BGP-15 treatment also improved diastolic function in ISO-treated rats. In isolated cardiomyocytes, BGP-15 prevented 100 nM ISO-induced aftercontractions. Here, we show that BGP-15 increases vagally mediated HRV, reduces arrhythmogenesis, enhances left ventricle relaxation, and suppresses the aftercontractions of cardiomyocytes. As the drug is well tolerated, it may have a clinical value in preventing fatal arrhythmias.

BGP-15 Protects against Doxorubicin-Induced Cell Toxicity via Enhanced Mitochondrial Function.

Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation. BGP-15 has a wide range of cytoprotective effects, including mitochondrial protection, but up to now, there is no information about any of its beneficial effects on DOX-induced cardiotoxicity. In this study, we investigated whether the protective effects of BGP-15 pretreatment are predominantly via preserving mitochondrial function, reducing mitochondrial ROS production, and if it has an influence on autophagy processes. H9c2 cardiomyocytes were pretreated with 50 µM of BGP-15 prior to different concentrations (0.1; 1; 3 µM) of DOX exposure. We found that BGP-15 pretreatment significantly improved the cell viability after 12 and 24 h DOX exposure. BGP-15 ameliorated lactate dehydrogenase (LDH) release and cell apoptosis induced by DOX. Additionally, BGP-15 pretreatment attenuated the level of mitochondrial oxidative stress and the loss of mitochondrial membrane potential. Moreover, BGP-15 further slightly modulated the autophagic flux, which was measurably decreased by DOX treatment. Hence, our findings clearly revealed that BGP-15 might be a promising agent for alleviating the cardiotoxicity of DOX. This critical mechanism appears to be given by the protective effect of BGP-15 on mitochondria.

Formulation and Evaluation of Transdermal Patches Containing BGP-15.

BGP-15 is an active ingredient with many advantages, e.g., beneficial cardiovascular and anti-inflammatory effects. The transdermal administration of BGP-15 has great potential, which has not been investigated yet, despite the fact that it is a non-invasive and safe form of treatment. The aim of our study was to formulate transdermal patches containing BGP-15 and optimize the production with the Box-Behnken design of experiment. The most optimal formulation was further combined with penetration enhancers to improve bioavailability of the active ingredient, and the in vitro drug release and in vitro permeation of BGP-15 from the patches were investigated. FTIR spectra of BGP-15, the formulations and the components were also studied. The most optimal formulation based on the tested parameters was dried for 24 h, with 67% polyvinyl alcohol (PVA) content and low ethanol content. The selected penetration enhancer excipients were not cytotoxic on HaCaT cells. The FTIR measurements and SEM photography proved the compatibility of the active substance and the vehicle; BGP-15 was present in the polymer matrix in dissolved form. The bioavailability of BGP-15 was most significantly enhanced by the combination of Transcutol and Labrasol. The in vitro permeation study confirmed that the formulated patches successfully enabled the transdermal administration of BGP-15.

Sustainable Transformation of Two Algal Species of Different Genera to High-Value Chemicals and Bioproducts.

This study investigates the potential of two algae species from different genera, namely the recently isolated Scenedesmus obliquus BGP and Porphyridium cruentum, from the perspective of their integral sustainable transformation to valuable substances. Conventional Soxhlet and environmentally friendly supercritical fluid extraction were applied to recover oils from the species. The extracts were characterized through analytical techniques, such as GC-Fid and LC-MS/MS, which allowed their qualitative and quantitative differentiation. Thus, P. cruentum oils contained up to 43% C20:4 and C20:5 fatty acids, while those of S. obliquus BGP had only residual amounts. The LC-MS/MS analysis of phenolic compounds in the S. obliquus BGP and P. cruentum extracts showed higher content of 3-OH-4-methoxybenzoic acid and kaempferol 3-O-glycoside in the former and higher amounts of ferulic acid in the latter. Total phenolic content and antioxidant activity of the oils were also determined and compared. The compositional analysis of the oil extracts revealed significant differences and varying potentialities based on their genera and method of extraction. To the best of our knowledge our work is unique in providing such detailed information about the transformation prospects of the two algae species to high-value chemicals and bioproducts.

A novel promising diagnostic candidate selected by screening the transcriptome of Babesia gibsoni (Wuhan isolate) asexual stages in infected beagles.

BACKGROUND: Babesia gibsoni is one of the causative agents of canine babesiosis worldwide. Some dogs infected with B. gibsoni show severe clinical signs with progressive anemia, hemoglobinuria and splenomegaly. However, most infected dogs present a state of chronic infection and thereby may be a persistent pathogen carrier, increasing the risk of pathogen spreading. To date, little is known about this pathogen, with genomic and transcriptomic data in particular generally unavailable. This lack of knowledge extensively limits the development of effective diagnostic strategies and vaccines. METHODS: High-throughput RNA sequencing of total RNA of B. gibsoni asexual stages collected from infected beagles was performed. The unigenes were annotated in seven databases. The genes were sorted according to their fragments per kilobase per million (FPKM) value, which was used as an indicator for expression level. The gene with the highest FPKM value was cloned from the genome of B. gibsoni and further tested for immunogenicity, cellular localization and efficacy as a potential diagnostic candidate for detecting B. gibsoni in sera collected from beagles. RESULTS: A total of 62,580,653 clean reads were screened from the 64,336,475 raw reads, and the corresponding 70,134 transcripts and 36,587 unigenes were obtained. The gene with the highest FPKM value was screened from the unigenes; its full length was 1276 bp, and it was named BgP30. The BgP30 gene comprised three exons and two introns, with a 786-bp open reading frame, and encoded 261 amino acids with a predicted molecular weight of 30 kDa. The cellular localization assay confirmed the existence of P30 protein in B. gibsoni parasites. Moreover, P30 was detected in the serum of experimentally B. gibsoni-infected beagles, from 15 days up to 422 days post-infection, suggesting its usefulness as a diagnostic candidate for both acute and chronic infections. CONCLUSIONS: We sequenced the transcriptome of B. gibsoni asexual stages for the first time. The BgP30 gene was highly expressed in the transcriptome screening experiments, with further studies demonstrating that it could induce immune response in B. gibsoni-infected dogs. These results lead us to suggest that bgP30 may be a good diagnostic candidate marker to detect both acute and chronic B. gibsoni infections.

Corrigendum: Improved survival and retinal function of aging ZDF rats in long-term, uncontrolled diabetes by BGP-15 treatment.

[This corrects the article DOI: 10.3389/fphar.2021.650207.].

Enhanced production of IL-2 from anti-CD3 antibody-stimulated mouse spleen cells by artepillin C, a major component of Brazilian green propolis.

OBJECTIVES: In this report, we attempt to clarify the immune modulatory effects of Brazilian green propolis (BGP) and its major component, artepillin C, on the cytokine production of anti-CD3 antibody-stimulated mouse spleen cells. We also estimate the physiological mechanism affecting artepillin C's upon the cells. METHODS: Male C3H/HeN mouse spleen cells stimulated by antiCD3 monoclonal antibody were co-cultured with BGP, artepillin C, and HC030031, a transient receptor potential ankyrin 1 (TRPA1) Ca2+ channel antagonist. The synthesis of interferon (IFN)-γ, interleukin (IL)-6, IL-17, IL-4, IL-10, and IL-2 was assayed by enzyme-linked immunoassay. The expression of IL-2 mRNA and the protein product were examined by reverse transcription-quantitative polymerase chain reaction and Western blot analyses, respectively. RESULTS: The production of IL-2 was markedly enhanced, while that of IL-4 and IL-10 was not significantly affected; by contrast, the production of IFN-γ, IL-6, and IL-17 was significantly reduced in the antibody-stimulated spleen cells treated with BGP at a non-cytostatic concentration. These effects were reproduced in the cells treated with artepillin C. The expression of IL-2 mRNA was unaffected; however, that of the protein was significantly enhanced in the artepillin C-treated cells compared to untreated control cells. The enhancement of protein expression and the production of IL-2 by artepillin C was significantly alleviated by adding HC030031. CONCLUSIONS: Artepillin C is an important regulator of cytokine synthesis from activated spleen cells. The agent specifically augmented the expression of IL-2 via the Ca2+-permeable cation channel, TRPA1, at least in part, at the translational or secretion levels.

Focal adhesion kinase inhibitors prevent osteoblast mineralization in part due to suppression of Akt-mediated stabilization of osterix.

Focal Adhesion Kinase (FAK) is an important regulator of tumor cell proliferation, survival and metastasis. As such it has become a therapeutic target of interest in cancer. Previous studies suggested that use of FAK tyrosine kinase inhibitors (TKIs) blocks osteolysis in in vivo models of bone metastasis. However, from these studies it was not clear whether FAK TKIs blocked bone degradation by osteoclasts or also promoted bone formation by osteoblasts. In this study we evaluated whether use of the FAK TKI PF-562,271 affected the differentiation of pre-osteoblasts, or activity of mature differentiated osteoblasts. MC3T3-E1 pre-osteoblastic cells were treated with various doses of PF-562,271 following 3 or 10 days of differentiation which led to the inhibition of alkaline phosphatase (ALP) expression and reduced viable cell numbers in a dose-dependent manner. MC3T3-E1 cells which had been differentiated for 21 days prior to treatment with PF-562,271 showed a dose dependent decrease in mineralization as assessed by Alizarin Red staining, with concomitant decreased expression of ALP which is known to facilitate the bone mineralization activity of osteoblasts, however mRNA levels of the transcription factors RUNX2 and osterix which are important for osteoblast maturation and mineralization appeared unaffected at this time point. We speculated that this may be due to altered function of RUNX2 protein due to inhibitory phosphorylation by GSK3ß. We found treatment with PF-562,271 resulted in increased GSK3ß activity as measured by reduced levels of phospho-Ser9-GSK3ß which would result in phosphorylation and inhibition of RUNX2. Treatment of 21 day differentiated MC3T3-E1 cells with PF-562,271 in combination with GSK3ß inhibitors partially restored mineralization however this was not statistically significant. As we observed that FAK TKI also resulted in suppression of Akt, which is known to alter osterix protein stability downstream of RUNX2, we examined protein levels by western blot and found a dose-dependent decrease in osterix in FAK TKI treated differentiated MC3T3-E1 cells which is likely responsible for the reduced mineralization observed. Taken together our results suggest that use of FAK TKIs as therapeutics in the bone metastatic setting may block new bone formation as an off-target effect and thereby exacerbate the defective bone regulation that is characteristic of the bone metastatic environment.

Effects of fluoride on the proliferation and activation of osteoblasts by regulating methylation of the DNA repair genes MGMT and MLH1.

INTRODUCTION: Fluoride can induce the proliferation and activation of osteoblasts, resulting in skeletal fluorosis progression; however, the specific mechanism is unclear. METHODS: Cell proliferation was examined using the MTT assay. Flow cytometry was performed to detect the cell cycle distribution. Alkaline phosphatase (ALP) was calculated to evaluate bone formation and turnover. Gene methylation was examined using the MSP assay. mRNA and protein expression levels were assessed using qRT-PCR and Western blot assays. RESULTS: Low-concentration NaF treatment promoted the cell cycle progression of osteoblasts to S-phase, thus accelerating cell proliferation and activation in a concentration-dependent manner. In addition, the methylation of the MGMT and MLH1 genes was increased, and their mRNA expression was reduced. Furthermore, the DNA methyltransferase inhibitor 5-AZA-dC suppressed cell viability, cell number in S-phase, ALP activity and osteogenesis-related protein levels in osteoblasts treated with low doses of NaF. Meanwhile, 5-AZA-dC suppressed the increase in MGMT and MLH1 gene methylation in osteoblasts treated with low doses of NaF, leading to enhanced expression of MGMT and MLH1 mRNA. CONCLUSION: NaF treatment led to methylation of the DNA repair genes MGMT and MLH1 in osteoblasts, resulting in cell proliferation and activation and causing the development of skeletal fluorosis.

Cardioprotective Role of BGP-15 in Ageing Zucker Diabetic Fatty Rat (ZDF) Model: Extended Mitochondrial Longevity.

Impaired mitochondrial function is associated with several metabolic diseases and health conditions, including insulin resistance and type 2 diabetes (T2DM), as well as ageing. The close relationship between the above-mentioned diseases and cardiovascular disease (CVD) (diabetic cardiomyopathy and age-related cardiovascular diseases) has long been known. Mitochondria have a crucial role: they are a primary source of energy produced in the form of ATP via fatty acid oxidation, tricarboxylic acid (TCA) cycle, and electron transport chain (ETC), and ATP synthase acts as a key regulator of cardiomyocyte survival. Mitochondrial medicine has been increasingly discussed as a promising therapeutic approach in the treatment of CVD. It is well known that vitamin B3 as an NAD+ precursor exists in several forms, e.g., nicotinic acid (niacin) and nicotinamide (NAM). These cofactors are central to cellular homeostasis, mitochondrial respiration, ATP production, and reactive oxygen species generation and inhibition. Increasing evidence suggests that the nicotinic acid derivative BGP-15 ((3-piperidine-2-hydroxy-1-propyl)-nicotinic amidoxime) improves cardiac function by reducing the incidence of arrhythmias and improves diastolic function in different animal models. Our team has valid reasons to assume that these cardioprotective effects of BGP-15 are based on its NAD+ precursor property. Our hypothesis was supported by an animal experiment where ageing ZDF rats were treated with BGP-15 for one year. Haemodynamic variables were measured with echocardiography to detect diabetic cardiomyopathy (DbCM) and age-related CVD as well. In the ZDF group, advanced HF was diagnosed, whereas the BGP-15-treated ZDF group showed diastolic dysfunction only. The significant difference between the two groups was supported by post-mortem Haematoxylin and eosin (HE) and Masson's trichrome staining of cardiac tissues. Moreover, our hypothesis was further confirmed by the significantly elevated Cytochrome c oxidase (MTCO) and ATP synthase activity and expression detected with ELISA and Western blot analysis. To the best of our knowledge, this is the first study to demonstrate the protective effect of BGP-15 on cardiac mitochondrial respiration in an ageing ZDF model.

Nicotinic-acid derivative BGP-15 improves diastolic function in a rabbit model of atherosclerotic cardiomyopathy.

BACKGROUND AND PURPOSE: The small molecule BGP-15 has been reported to alleviate symptoms of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. EXPERIMENTAL APPROACH: Rabbits were maintained on standard chow (control) or atherogenic diet (hypercholesterolemic) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed and key molecules in the protein kinase G (PKG) pathway were examined by enzyme-linked immunosorbent assay (ELISA) and western blot. Passive force generation was investigated in skinned cardiomyocytes. KEY RESULTS: Both acute and chronic BGP-15 treatments improved the diastolic performance of the diseased heart. However, vasorelaxation and serum lipid markers were unaffected. Myocardial cyclic guanosine monophosphate (cGMP) levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group and PDE1 was inhibited. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased and PKG-dependent N2B-titin phosphorylation elevated. CONCLUSIONS AND IMPLICATIONS: BGP-15 treatment improves diastolic function, reduces cardiomyocyte stiffness and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG pathway. As BGP-15 has been proven to be safe, it may be clinically useful in the treatment of diastolic dysfunction.

Nicotinic Amidoxime Derivate BGP-15, Topical Dosage Formulation and Anti-Inflammatory Effect.

BGP-15 is a Hungarian-developed drug candidate with numerous beneficial effects. Its potential anti-inflammatory effect is a common assumption, but it has not been investigated in topical formulations yet. The aim of our study was to formulate 10% BGP-15 creams with different penetration enhancers to ensure good drug delivery, improve bioavailability of the drug and investigate the potential anti-inflammatory effect of BGP-15 creams in vivo. Since the exact mechanism of the effect is still unknown, the antioxidant effect (tested with UVB radiation) and the ability of BGP-15 to decrease macrophage activation were evaluated. Biocompatibility investigations were carried out on HaCaT cells to make sure that the formulations and the selected excipients can be safely used. Dosage form studies were also completed with texture analysis and in vitro release with Franz diffusion chamber apparatus. Our results show that the ointments were able to reduce the extent of local inflammation in mice, but the exact mechanism of the effect remains unknown since BGP-15 did not show any antioxidant effect, nor was it able to decrease LPS-induced macrophage activation. Our results support the hypothesis that BGP-15 has a potential anti-inflammatory effect, even if it is topically applied, but the mechanism of the effect remains unclear and requires further pharmacological studies.

Whitening and inhibiting NF-κB-mediated inflammation properties of the biotransformed green ginseng berry of new cultivar K1, ginsenoside Rg2 enriched, on B16 and LPS-stimulated RAW 264.7 cells.

BACKGROUND: Main bioactive constituents and pharmacological functions of ripened red ginseng berry (Panax ginseng Meyer) have been frequently reported. Yet, the research gap targeting the beneficial activities of transformed green ginseng berries has not reported elsewhere. METHODS: Ginsenosides of new green berry cultivar K-1 (GK-1) were identified by HPLC-QTOF/MS. Ginsenosides bioconversion in GK-1 by bgp1 enzyme was confirmed with HPLC and TLC. Then, mechanisms of GK-1 and ß-glucosidase (bgp1) biotransformed GK-1 (BGK-1) were determined by Quantitative Reverse Transcription-Polymerase Chain Reaction and Western blot. RESULTS: GK-1 possesses highest ginsenosides especially ginsenoside-Re amongst seven ginseng cultivars including (Chunpoong, Huangsuk, Kumpoong, K-1, Honkaejong, Gopoong, and Yunpoong). Ginseng root's biomass is not affected with the harvest of GK-1 at 3 weeks after flowering period. Then, Re is bio-converted into a promising pharmaceutical effect of Rg2 via bgp1. According to the results of cell assays, BGK-1 shows decrease of tyrosinase and melanin content in α-melanocyte-stimulating hormone challenged-murine melanoma B16 cells. BGK-1 which is comparatively more effective than GK-1 extract shows significant suppression of the nuclear factor (NF)-κB activation and inflammatory target genes, in LPS-stimulated RAW 264.7 cells. CONCLUSION: These results reported effective whitening and anti-inflammatory of BGK-1 as compared to GK-1.

BGP-15 Inhibits Hyperglycemia-Aggravated VSMC Calcification Induced by High Phosphate.

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.