Additional Anti-inflammatory Effects Research Articles

Atrial Fibrosis and Inflammation inPostoperative Atrial Fibrillation: Comparative Effects of Amiodarone, Colchicine, or Exosomes.

Extracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear. The purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis. Specifically, we aimed to assess the efficacy of amiodarone (a classic antiarrhythmic drug), colchicine (an anti-inflammatory agent), and EVs derived from human heart-derived cells, which possess anti-inflammatory and antifibrotic properties, on AF induction, inflammation, and fibrosis progression. Heart-derived cells were cultured from human atrial appendages under serum-free xenogen-free conditions. Middle-aged Sprague Dawley rats were randomized into different groups, including sham operation, sterile pericarditis with amiodarone treatment, sterile pericarditis with colchicine treatment (2 dose levels), and sterile pericarditis with intra-atrial injection of EVs or vehicle. Invasive electrophysiological testing was performed 3days after surgery before sacrifice. Sterile pericarditis increased the likelihood of inducing AF. Colchicine and EVs exhibited anti-inflammatory effects, but only EV treatment significantly reduced AF probability, whereas colchicine showed a positive trend without statistical significance. EVs and high-dose colchicine reduced atrial fibrosis by 46 ± 2% and 26 ± 2%, respectively. Amiodarone prevented AF induction but had no effect on inflammation or fibrosis. In this study, both amiodarone and EVs prevented AF, whereas treatment with colchicine was ineffective. The additional anti-inflammatory and antifibrotic effects of EVs suggest their potential as a comprehensive therapeutic approach for AF prevention, surpassing the effects of amiodarone or colchicine.

Bioactive Fractions Isolated from Harungana madagascariensis Lam. and Psorospermum aurantiacum Engl. Regulate Collagen and Melanin Biosynthesis Gene Expression in UVB-Irradiated Cells with Additional Anti-Inflammatory Potential.

Harungana madagascariensis (HM) and Psorospermum aurantiacum (PA), used traditionally for skin care, have been reported to upregulate the expression of intracellular antioxidant genes, thereby preventing melanoma and protecting fibroblast cell lines from Ultraviolet B (UVB)-induced intracellular oxidative stress. This investigation aimed to identify major compounds in bioactive fractions using bioassay- guided fractionation. The anti-inflammatory effect of fractions was determined by measuring their inhibitory activity on 15-lipoxygenase and nitric oxide (NO) in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Additionally, the anti-aging efficacy of the fractions was determined by assessing the expression of markers for the aging process, i.e., expression of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), procollagen type-1 (COL1A1), and matrix metalloproteinase- 1 (MMP-1) in UVB-induced photoaging in skin cell-lines. Furthermore, UHPLCMS- based identification of the bioactive compounds from the most prominent fraction was also carried out. Hexane fraction of HM significantly inhibited (p <0.05) the 15-lipoxygenase (IC50 = 46.80 μg/mL) and NO production (IC50 = 66.55 μg/mL), whereas hexane fraction of PA was effective (p <0.05) in inhibiting 15-lipoxygenase activity (IC50 = 27.55 μg/mL). Furthermore, the hexane fraction of HM and methanol fraction of PA were significantly effective (p <0.05) in reverting the UVB-mediated altered expressions of MMP-1, TYR, TRP-1, and COL1A1. Furthermore, hexane fraction of HM revealed the presence of harunganin and betulinic acid, whereas vismion D, vismin, kenganthranol B, and bianthrone 1a were identified from the methanol fraction of PA. Overall, the hexane fraction of HM and methanol fraction of PA displayed effective anti-aging activities, with additional anti-inflammatory effects.

Natural ursolic acid based self-therapeutic polymer as nanocarrier to deliver natural resveratrol for natural therapy of acute kidney injury

Acute kidney injury (AKI) is a common kidney disease associated with excessive reactive oxygen species (ROS). Unfortunately, due to the low kidney targeting and undesired side effects, the existing antioxidant and anti-inflammatory drugs are unavailable for AKI management in clinic. Therefore, it’s essential to develop effective nanodrugs with high renal targeting and biocompatibility for AKI treatment. Herein, we reported a novel nanodrug for AKI treatment, utilizing poly(ursolic acid) (PUA) as a bioactive nanocarrier and resveratrol (RES) as a model drug. The PUA polymer was synthesized form ursolic acid with intrinsic antioxidant and anti-inflammatory activities, and successfully encapsulated RES through a nanoprecipitation method. Subsequently, we systemically investigated the therapeutic potential of RES-loaded PUA nanoparticles (PUA NPs@RES) against AKI. In vitro results demonstrated that PUA NPs@RES effectively scavenged ROS and provided substantial protection against H2O2-induced cellular damage. In vivo studies revealed that PUA NPs significantly improved drug accumulation in the kidneys and exhibited favorable biocompatibility. Furthermore, PUA NPs alone exhibited additional anti-inflammatory and antioxidant effect, synergistically enhancing therapeutic efficacy in AKI mouse models when combined with RES. Overall, our study successfully developed an effective nanodrug using self-therapeutic nanocarriers, presenting a promising option for the treatment of AKI.Graphical abstract

Study of the effect of bezafibrate with ginkgo biloba extracts in an animal model of hepatotoxicity induced by doxorubicin

This study aimed to evaluate the hepatoprotective effect of combining bezafibrate with ginkgo biloba in doxorubicin-induced hepatotoxicity in rats. Thirty Wister albino rats were allocated into five groups: The negative control group, the positive control group, both received 1 ml of D.W, bezafibrate group received (100 mg/kg), ginkgo biloba group received (60 mg/kg) and the fifth group received bezafibrate + ginkgo biloba. All the treatments were for 14 days along with doxorubicin on days 11–14 except for the negative control. Blood samples were used for the measurement of ALT, AST, ALP, total protein, total bilirubin, albumin, globulin, GSH, catalase, and IL-6. Liver tissue was sent for histopathological examination. The combination of ginkgo biloba and bezafibrate significantly decreased AST, ALP, AST/ALT ratio, albumin/globulin ratio, and IL-6 with significant elevations of catalase, and GSH. The combination group produced more hepatoprotection. This could be attributed to the additive anti-inflammatory and antioxidant effects of the combination.

Chondroitin Sulphate-Chitosan polyelectrolyte complexes for etorocoxib transdermal delivery: in silico, in vitro and in vivo studies

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects around 1% globally leading to joint inflammation and disability. Etorocoxib (ETR) is a potent COX-2 inhibitor traditionally used orally to alleviate RA induced inflammation, yet it causes hepatic side effects on prolonged use. This study aims for in silico optimization of ETR polyelectrolyte complex (PEC) utilizing chondroitin sulphate (CS) and chitosan (CH) for transdermal delivery to RA-inflamed joints with a synergistic anti-inflammatory action owing to CS. An artificial neural network (ANN) combined with 22 factorial design was used to optimize the PEC formula according to particle size (PS) and entrapment efficiency (%EE) by varying CS and CH concentrations. The optimum ETR PEC was incorporated in a gel and examined for its in vitro release, ex vivo permeation, in vivo inflammatory biomarkers, and histopathological evaluation in rats. The optimized formula (F3) with 0.1 CH% w/w and 0.5 CS %w/w showed a PS of 214.98 ± 17.24 nm, %EE 75.31 ± 1.67%, and enhanced in vitro release profile, ex vivo permeation and in vivo anti-inflammatory effect compared to ETR gel via suppressing the expression of IL-6, TNF-α, and TGF-β pro-inflammatory cytokines as well as the additional anti-inflammatory effect of CS. In conclusion, ETR-PEC gel holds promise as transdermal therapy for managing RA-induced inflammation.

Preservation solution Custodiol containing human alpha-1-antitrypsin improves graft recovery after prolonged cold ischemic storage in a rat model of heart transplantation.

The shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation therapy to treat emphysema due to severe AAT deficiency. Evidence demonstrates its additional anti-inflammatory and tissue-protective effects. We hypothesized that adding human AAT in a preservation solution reduces graft dysfunction in a rat model of HTX following extended cold ischemic storage. The hearts from isogenic Lewis donor rats were explanted, stored for either 1h or 5h in cold Custodiol supplemented with either vehicle (1h ischemia, n=7 or 5h ischemia, n=7 groups) or 1 mg/ml AAT (1h ischemia+AAT, n=7 or 5h ischemia+AAT, n=9 groups) before heterotopic HTX. Left-ventricular (LV) graft function was evaluated in vivo 1.5h after HTX. Immunohistochemical detection of myeloperoxydase (MPO) was performed in myocardial tissue and expression of 88 gene quantified with PCR was analyzed both statistical and with machine-learning methods. After HTX, LV systolic function (dP/dtmax 1h ischemia+AAT 4197 ± 256 vs 1h ischemia 3123 ± 110; 5h ischemia+AAT 2858 ± 154 vs 5h ischemia 1843 ± 104mmHg/s, p<0.05) and diastolic function (dP/dtmin 5h ischemia+AAT 1516 ± 68 vs 5h ischemia 1095 ± 67mmHg/s, p<0.05) at an intraventricular volume of 90µl were improved in the AAT groups compared with the corresponding vehicle groups. In addition, the rate pressure product (1h ischemia+AAT 53 ± 4 vs 1h ischemia 26 ± 1; 5h ischemia+AAT 37 ± 3 vs 5h ischemia 21 ± 1mmHg*beats/min at an intraventricular volume of 90µl; p<0.05) was increased in the AAT groups compared with the corresponding vehicle groups. Moreover, the 5h ischemia+AAT hearts exhibited a significant reduction in MPO-positive cell infiltration in comparison to the 5h ischemia group. Our computational analysis shows that ischemia+AAT network displays higher homogeneity, more positive and fewer negative gene correlations than the ischemia+placebo network. We provided experimental evidence that AAT protects cardiac grafts from prolonged cold ischemia during HTX in rats.

In vitro antiproliferative, anti-inflammatory effects and molecular docking studies of natural compounds isolated from Sarcocephalus pobeguinii (Hua ex Pobég).

Background: Sarcocephalus pobeguinii (Hua ex Pobég) is used in folk medicine to treat oxidative-stress related diseases, thereby warranting the investigation of its anticancer and anti-inflammatory properties. In our previous study, the leaf extract of S. pobeguinii induced significant cytotoxic effect against several cancerous cells with high selectivity indexes towards non-cancerous cells. Aim: The current study aims to isolate natural compounds from S. pobeguinii, and to evaluate their cytotoxicity, selectivity and anti-inflammatory effects as well as searching for potential target proteins of bioactive compounds. Methods: Natural compounds were isolated from leaf, fruit and bark extracts of S. pobeguinii and their chemical structures were elucidated using appropriate spectroscopic methods. The antiproliferative effect of isolated compounds was determined on four human cancerous cells (MCF-7, HepG2, Caco-2 and A549 cells) and non-cancerous Vero cells. Additionally, the anti-inflammatory activity of these compounds was determined by evaluating the nitric oxide (NO) production inhibitory potential and the 15-lipoxygenase (15-LOX) inhibitory activity. Furthermore, molecular docking studies were carried out on six putative target proteins found in common signaling pathways of inflammation and cancer. Results: Hederagenin (2), quinovic acid 3-O-[α-D-quinovopyranoside] (6) and quinovic acid 3-O-[β-D-quinovopyranoside] (9) exhibited significant cytotoxic effect against all cancerous cells, and they induced apoptosis in MCF-7 cells by increasing caspase-3/-7 activity. (6) showed the highest efficacy against all cancerous cells with poor selectivity (except for A549 cells) towards non-cancerous Vero cells; while (2) showed the highest selectivity warranting its potential safety as a chemotherapeutic agent. Moreover, (6) and (9) significantly inhibited NO production in LPS-stimulated RAW 264.7 cells which could mainly be attributed to their high cytotoxic effect. Besides, the mixture nauclealatifoline G and naucleofficine D (1), hederagenin (2) and chletric acid (3) were active against 15-LOX as compared to quercetin. Docking results showed that JAK2 and COX-2, with the highest binding scores, are the potential molecular targets involved in the antiproliferative and anti-inflammatory effects of bioactive compounds. Conclusion: Overall, hederagenin (2), which selectively killed cancer cells with additional anti-inflammatory effect, is the most prominent lead compound which may be further investigated as a drug candidate to tackle cancer progression.

Effects of combined cannabidiol (CBD) and hops (Humulus lupulus) terpene extract treatment on RAW 264.7 macrophage viability and inflammatory markers

This study investigates the potential of cannabidiol (CBD), one major cannabinoid of the plant Cannabis sativa, alone and in combination with a terpene-enriched extract from Humulus lupulus (“Hops 1”), on the LPS-response of RAW 264.7 macrophages as an established in vitro model of inflammation. With the present study, we could support earlier findings of the anti-inflammatory potential of CBD, which showed a dose-dependent [0–5 µM] reduction in nitric oxide and tumor necrosis factor-alpha (TNF-α) released by LPS-stimulated RAW 264.7 macrophages. Moreover, we observed an additive anti-inflammatory effect after combined CBD [5 µM] and hops extract [40 µg/mL] treatment. The combination of CBD and Hops 1 showed effects in LPS-stimulated RAW 264.7 cells superior to the single substance treatments and akin to the control hydrocortisone. Furthermore, cellular CBD uptake increased dose-dependently in the presence of terpenes from Hops 1 extract. The anti-inflammatory effect of CBD and its cellular uptake positively correlated with terpene concentration, as indicated by comparison with a hemp extract containing both CBD and terpenes. These findings may contribute to the postulations for the so-called “entourage effect” between cannabinoids and terpenes and support the potential of CBD combined with phytomolecules from a non-cannabinoid source, such as hops, for the treatment of inflammatory diseases.

Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis.

Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects. To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start METHODS: We performed a comprehensive literature search of PubMed for relevant publications. International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental. With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.

Gliflozins Have an Anti-Inflammatory Effect on Renal Proximal Tubular Epithelial Cells in a Diabetic and Inflammatory Microenvironment In Vitro.

Inflammation is intimately involved in the pathogenesis of diabetic kidney disease. Inhibition of SGLT-2 by a specific class of drugs, gliflozins, has been shown to reduce inflammation and attenuate the progression of diabetic nephropathy, in addition to its main effect of inhibiting renal glucose reabsorption. We used highly purified human renal proximal tubular epithelial cells (PTCs) as an in vitro model to study the cellular response to a diabetic (high glucose) and inflammatory (cytokines) microenvironment and the effect of gliflozins. In this context, we investigated the influence of SGLT-2 inhibition by empa- and dapagliflozin (500 nM) on the expression of pro-inflammatory factors (IL-1β, IL-6, TNF-α, MCP-1, and ICAM-1). The results clearly indicate an anti-inflammatory effect of both gliflozins. Although induced expression of the four cytokines was only slightly attenuated, there was a clear effect on the expression of the adhesion molecule ICAM-1, a master regulator of cellular responses in inflammation and injury resolution. The induced expression of ICAM-1 mRNA was significantly reduced by approximately 13.5% by empagliflozin and also showed an inhibitory trend with dapagliflozin. However, induced ICAM-1 protein expression was significantly inhibited from 24.71 ± 1.0 ng/mL to 18.81 ± 3.9 (empagliflozin) and 19.62 ± 2.1 ng/mL (dapagliflozin). In conclusion, an additional anti-inflammatory effect of empa- and dapagliflozin in therapeutically observed concentrations was demonstrated in primary human PTCs in vitro.

RESULTS OF CYTOLOGICAL STUDY IN EXPERIMENTAL ANIMALS WITH AND WITHOUT TREATMENT OF ULCERATIVE NECROTIC GINGIVITIS WITH A COMPLEX OF DRUGS WITH ANTIOXIDANT PROPERTIES

Changes in the quantitative indicators of non-specific resistance systems of the body indicate a damage to homeostasis in the body and the development of a pathological process. The state of defense systems largely determines the course and provides a predictive characteristic of the intensity and effectiveness of treatment measures. In patients with inflammatory processes of periapical tissues, there is an imbalance of factors that characterize the state of local resistance of the oral cavity and the mucous membrane of the gums. Also, quantitative and qualitative changes in indicators of phagocytosis, chemotaxis of leukocytes, secretion of cytokines, immunoglobulins, and bactericidal activity of humoral factors of the body's defense were observed.&#x0D; Laboratory animals with experimental model of ulcerative-necrotic gingivitis by chemical burn were divided into three groups: intact, control, and experimental. Animals of the control group were not treated; in the experimental group, complex of drugs was applied to the ulcer surface, which included Thiotriazoline ointment, Zinc oxide, and 0.05% Chlorhexidine solution. In the selected periods of observation (3rd, 5th, 7th, and 10th days), cytological examination of smears was used to determine the adsorption reaction of microorganisms (ARM) by counting the number of bacteria adsorbed on the surface of each epithelial cell (based on 100 cells).&#x0D; At the beginning of the observation, sharp decrease in the number of highly differentiated cells was noted in the smears of animals of the control group, cells of the III stage of differentiation prevailed, and the IDC decreased to 67.52% of the level of intact animals. In all subsequent periods, animals of the control group showed a gradual increase in the IDC index due to an increase in cells in the V stage of differentiation on the surface of the ulcer. The CDI value was significantly different from the norm on the 5th day, with a value of 75.15% of the physiological level, and on the 7th day, with a value of 87.54%. Only on the 10th day was an unreliable difference from the average indicator with 99.13% to its value.&#x0D; In the experimental group, on the 3rd day, sharp and reliable decrease in the number of highly differentiated pools of epitheliocytes and the dominance of cells in the III stage of differentiation was observed, the number of which reached the value of 44.0±1.5%. As a result, at this time, the CDI value decreased relative to the indicator of intact animals to 69.85% of its level. At the end of the observation, the CDI value reliably exceeded the level of intact animals by 4.12%.&#x0D; The most significant decrease in the value of ARM in animals of the control group was detected on the 3rd day, which in percentage value was 76% of the value of intact animals. On the 5th day, the value of "ARM +" increased slightly (only by 4%) to 80% of the physiological norm, and on the 7th day by another 5.5% to 85.5%. Even at the end of the experiment, the "RAM +" indicator in the animals of the control group was significantly lower than that of the intact animals. It was equal to 90% of it.&#x0D; In the experimental group, unlike the control group, satisfactory state of local non-specific resistance in the area of the damaged mucosa was observed only on the 3rd and 5th days. The value of "ARM+" in these terms was only 79.46% and 83.6% of the value of intact animals, respectively. Due to the local effect of the developed complex of drugs, the state of non-specific resistance on the 7th day of observation reached a value corresponding to the "good" level. The "ARM +" percentage value increased to 93.6% of intact animals. At the end of the observation, it reached 97.87% of the physiological norm.&#x0D; Therefore, the cytological study's data coincided with the results of a visual examination of the course of healing of local gingivitis of chemical origin. Due to the additional local anti-inflammatory effect of the developed complex of drugs, it became possible to achieve the normalization of the damaged local non-specific reactivity of the oral mucosa faster (on average, for 3-4 days), and the stimulating regenerative effect promotes more rapid differentiation of epitheliocytes and complete restoration of the damaged area of the gums in a shorter time (on average, 2 -3 days) treatment terms.

Клінічна оцінка використання інгаляцій 6% N-ацетилцистеїну у 3% розчині NaCL (ФЛУ-АЦИЛ бронхо) в лікуванні дітей з гострим бронхітом

Purpose - to propose an optimization of treatment of acute bronchitis in children by introducing inhalation of FLU-ACIL broncho before therapy. Materials and methods. An open, prospective, multicenter, non-interventional, comparative (with active control) study with two therapeutic groups was conducted. The experience of therapy of 45 children with moderate acute bronchitis aged 2-12 years old was summarized. The main group included 30 children who received inhalation of Flu-Acyl Broncho in the complex treatment: 5 ml 2 times a day 3-4 hours before bedtime for 7-10 days; the comparison group included 15 children who received oral acetylcysteine/ambroxol for 7-12 days. If it is necessary, antipyretic therapy with ibuprofen or paracetamol was used. The period from the onset of the disease to participation in the study was about 2-4 days. The study did not include children with concomitant acute middle ear diseases, acute sinusitis, acute allergic diseases and children with symptoms of obstruction. The results of examination and treatment of patients were analyzed using the software package «Statistica 6.0 for Windows». Results and conclusions. Comprehensive treatment of acute bronchitis in children with the administration of the inhalation Flu-Acyl Broncho, sterile solution for nebulizer and instillation, has a positive clinical effect, leads to faster relief (p&lt;0.01) and disappearance (p&lt;0.05) of cough compared to oral mucolytics. The additional anti-inflammatory and mucolytic effect of the inhalation route of administration of Flu-Acyl Broncho on the nasopharyngeal mucosa improves the results of treatment of children with concomitant acute respiratory pathology of the upper respiratory tract. This is manifested in faster, compared to oral mucolytics, elimination of rhinitis (p&lt;0.001) and sore throat (p&lt;0.05). All studies were performed in accordance with the ethical principles adopted by the Declaration of Helsinki and Good Clinical Practice (GCP) for medical research conducted on human subjects. Approval was obtained from the ethics committee of the Children’s Clinical Hospital No. 5 of Sviatoshynskyi district of Kyiv. No conflict of interests was declared by the authors.

Photobiomodulation isolated or associated with adipose-derived stem cells allograft improves inflammatory and oxidative parameters in the delayed-healing wound in streptozotocin-induced diabetic rats.

The single and associated impressions of photobiomodulation (PBM) and adipose-derived stem cells (ADS) on stereological parameters (SP), and gene expression (GE) of some antioxidant and oxidative stressors of repairing injured skin at inflammation and proliferation steps (days 4 and 8) of a delayed healing, ischemic, and infected wound model (DHIIWM) were examined in type one diabetic (DM1) rats. DM1 was induced by administration of streptozotocin (40 mg/kg) in 48 rats. The DHIIWM was infected by methicillin-resistant Staphylococcus aureus (MRSA). The study comprised 4 groups (each, n = 6): Group 1 was the control group (CG). Group 2 received allograft human (h) ADSs transplanted into the wound. In group 3, PBM (890 nm, 80 Hz, 0.2 J/cm2) was emitted, and in group 4, a combination of PBM+ADS was used. At both studied time points, PBM+ADS, PBM, and ADS significantly decreased inflammatory cell count (p < 0.05) and increased granulation tissue formation compared to CG (p < 0.05). Similarly, there were lower inflammatory cells, as well as higher granulation tissue in the PBM+ADS compared to those of alone PBM and ADS (all, p < 0.001). At both studied time points, the GE of catalase (CAT) and superoxide dismutase (SOD) was remarkably higher in all treatment groups than in CG (p < 0.05). Concomitantly, the outcomes of the PBM+ADS group were higher than the single effects of PBM and ADS (p < 0.05). On day 8, the GE of NADPH oxidase (NOX) 1 and NOX4 was substantially less in the PBM+ADS than in the other groups (p < 0.05). PBM+ADS, PBM, and ADS treatments significantly accelerated the inflammatory and proliferative stages of wound healing in a DIIWHM with MRSA in DM1 rats by decreasing the inflammatory response, and NOX1 and 4 as well; and also increasing granulation tissue formation and SOD andCAT. The associated treatment of PBM+ADS was more effective than the individual impacts of alone PBM and ADS because of the additive anti-inflammatory and proliferative effects of PBM plus ADS treatments.

Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition

The intracellular lipid amidases, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA), terminate the actions of anandamide and palmitoylethanolamide (PEA), two antinociceptive and anti-inflammatory lipid-derived mediators. Here we show, confirming prior research, that small-molecule inhibitors of peripheral FAAH (compound URB937) and systemic NAAA (compound ARN19702) individually attenuate, in male CD-1 mice, pain-related behaviors and paw inflammation in the formalin and carrageenan tests. More importantly, isobolographic analyses revealed that the combination of URB937 and ARN19702 produced substantial synergistic (greater than additive) antinociceptive effects in both models as well as additive anti-inflammatory effects in the carrageenan test. Together, the findings uncover a functional interplay between FAAH and NAAA substrates in the control of nociception, which might be exploited clinically to develop safe and effective pain management strategies

Prenylated Flavonoids in Topical Infections and Wound Healing.

The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 µg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability.

Female-specific neuroprotection after ischemic stroke by vitronectin-focal adhesion kinase inhibition

We found that blood vitronectin (VTN) leaks into the brain and exacerbates tissue loss after stroke by increasing pro-inflammatory IL-6 expression in female, but not male, mice. VTN signals through integrins and downstream focal adhesion kinase (FAK). Here, a two day systemic treatment with a small molecule FAK inhibitor starting 6 h after middle cerebral artery occlusion reduced ipsilateral brain injury size by ∼40–45% at 7 and 14 d, as well as inflammation and motor dysfunction in wild-type female, but not male, mice. FAK inhibition also reduced IL-6 expression in the injured female striatum at 24 h by 62%. Inducible selective gene deletion of FAK in astrocytes also reduced acute IL-6 expression by 72% only in females, and mitigated infarct size by ∼80% and inflammation at 14 d after stroke. Lastly, VTN−/− females had better outcomes, but FAK inhibitor treatment had no additional protective or anti-inflammatory effects. Altogether, this suggests that VTN is detrimental in females primarily through FAK and that FAK inhibition provides neuroprotection (cerebroprotection) by reducing VTN-induced IL-6 expression in astrocytes. Thus, VTN signaling can be targeted to mitigate harmful inflammation with relevance to treatments for women with ischemic stroke, who often have worse outcomes than men.

Dapagliflozin associated to sacubitril/valsartan and relationship with cardioprotection in human cardiac cells exposed to doxorubicin and HER2-blocking agents through MyD88, NLRP3 mediated pathways.

587 Background: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co-transporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity. Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces intracellular Ca2+ overload (-68,4% vs cells treated only to anticancer drugs; p&lt;0,001), lipid peroxidation (mean reduction of 57-63,4 % compared to cells exposed only to anticancer drugs; p&lt;0,05). The expression of MyD88, NLRP3 and NF-kB were strongly reduced after treatment with dapagliflozin and LCZ-696 (-52,5, -43,7 and -57,3 % vs cells exposed only to anticancer drugs, respectively; p&lt;0.05). Notably, combination of dapagliflozin and LCZ-696 enhanced the expression Of IL-10; contrary, pro-inflammatory cytokines were reduced, such as IL-1α, IL-1β, IL-6, IL-8, IL17-α and IL-18 (p&lt;0.05). Conclusions: During exposure to doxorubicin and trastuzumab, dapagliflozin associated to LCZ-696 exerts additive cardioprotective and anti-inflammatory effects compared to each drug alone. Their properties are mediated by the reduction of iCa2+ content that consequently reduces peroxidation and NLRP3- MyD88 expression. These results indicating the potential use of SGLT-2 inhibitors associated to LCZ696 in preclinical models of cardiotoxicity.

ОТДЕЛЬНЫЕ АСПЕКТЫ ЛЕЧЕНИЯ ПАЦИЕНТОВ С ВПЕРВЫЕ ВЫЯВЛЕННЫМ ТУБЕРКУЛЕЗОМ ЛЕГКИХ С МНОЖЕСТВЕННОЙ ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ В СОЧЕТАНИИ И ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНЬЮ ЛЕГКИХ: В ФОКУСЕ ИНГАЛЯЦИОННЫЕ ГЛЮКОКОРТИКОСТЕРОИДЫ

Introduction. The problem of treating tuberculosis (TB) remains relevant, due to the growth of drug-resistant forms of mycobacterium tuberculosis and an increase in the incidence of TB in persons with comorbid bronchopulmonary pathology, which requires comprehensive management of this category of patients, with mandatory drug correction of concomitant pathology. Aim. The aim of this study was to assess the effect of inhaled glucocorticosteroids (budesonide / formoterol 160 / 4.5 in an Inhaler device) on the efficacy of TB therapy in patients with newly diagnosed multidrug-resistant tuberculosis (MDR) who developed in the presence of chronic obstructive pulmonary disease (COPD). Material and methods. A simple, prospective, comparative study in accordance with the inclusion criteria included 40 patients admitted to an anti-tuberculosis dispensary with newly diagnosed MDR tuberculosis with COPD. The diagnosis of TB and COPD was confirmed using radiographic, functional and laboratory research methods. Group 1, age Me (25; 75) 55.5 (46; 58) years - 22 patients with MDR + COPD tuberculosis who, simultaneously with TB chemotherapy, received a short-acting M-anticholinergic blocker, 2 inhalations 4 times a day, group 2, age 54.5 (51; 58) years - 18 patients with MDR + COPD tuberculosis, simultaneously with TB chemotherapy received a combination of ICS with a long-acting bronchodilator (beta-2-agonist (LABA)), budesonide + formoterol 160 / 4.5 μg dose - 2 inhalations 2 times a day (in an inhaler device). Duration of observation is 9 months. Results and discussion. After 9 months of observation, closure of decay cavities in 63.6% in group 1 and 83.3% in group 2 (χ² = 0.3; p = 0.581), smear negativity in 90.9% of cases in group 1 and in 100, 0% in group 2, respectively (χ² = 0.04 p = 0.834), abacillated 63.3% and 100.0% in groups 1 and 2, respectively (χ² = 0.46; p = 0.496). Against the background of the use of ICS in the intensive phase of TB chemotherapy simultaneously with antibiotic therapy, there was a decrease in the time of abacillation and closure of decay cavities in comparison with the group that did not receive ICS. At the same time in broncholics, the use of ICS made it possible to quickly stop the broncho-obstructive syndrome, improve the quality of life and compliance with long-term anti-tuberculosis therapy. An additional nonspecific anti-inflammatory effect of ICS promoted the active resorption of infiltrative changes and the cure of a specific process, reducing the duration of the main course of treatment, including in patients with MDR. Conclusion. Patients of the anti-tuberculosis dispensary with concomitant bronchopulmonary pathology need complex treatment aimed at correcting comorbid conditions, simultaneously with chemotherapy for tuberculosis. The use of ICS in addition to long-acting bronchodilators (LABA, LDAH) in patients with COPD for the correction of broncho-obstructive syndrome in the intensive phase of TB treatment can reduce the time of smear negativity, abacillation and closure of decay cavities.

Effects of acute aerobic exercise on cytokines, klotho, irisin, and vascular endothelial growth factor responses in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes cartilage and bone damage as well as disability. AIMS : The aim of this study was to examine the effects of acute aerobic exercise on cytokines such as serum interleukin-6 (IL-6), interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α) and irisin, vascular endothelial growth factor(VEGF) and klotho in RA patients. METHODS: Forty RA patient and 40 healthy volunteers of the same age participated in this study. All participants walked on the treadmill for 30 minutes at 60-80% of maximal heart rate. Blood samples were taken before and immediately after the exercise. Serum levels of IL-6, IL1β, TNF-α and irisin, VEGF and klotho were measured by enzyme-linked immunosorbent analysis. RESULTS: Baseline levels of inflammatory cytokines, irisin, VEGF and klotho were found to be higher in RA patients compared to the control group. In both groups, there was an increase in serum klotho levels after exercise compared to baseline (p<0.05), while a decrease in IL1β, TNF-α levels were observed. While serum VEGF level decreased in RA group, it increased in the control group(p<0.05). Irisin levels decreased in both groups. IL-6 level did not change in the control group, while it increased in RA group. A single exercise session had an acute anti-inflammatory effect in RA patients. It can be concluded that acute aerobic exercise can be beneficial for patients with RA through cytokine, irisin, klotho and VEGF levels, and also it can be safely implemented to the RA rehabilitation program for additional anti-inflammatory effects. Trial registration ClinicalTrials.gov: NCT04439682.

Association of dietary and plasma carotenoids with urinary F2-isoprostanes.

Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations between carotenoids and biomarkers of oxidative stress or inflammation. From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35-74. Post-menopausal participants (n = 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of β-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were also measured. Since the biomarker 8-iso-PGF2α can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF2α to prostaglandin F2α ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations. Total plasma carotenoids were inversely associated with 8-iso-PGF2α-M concentrations (P for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and β-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF2α; Phighest vs. lowest quartile = 0.04 and P for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF2α, suggesting an additional anti-inflammatory effect. Supplemental β-carotene was inversely associated with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF2α. Dietary carotenoids were not associated with either biomarker. Plasma carotenoids and supplemental β-carotene were associated with lower concentrations of 8-iso-PGF2α metabolite. Plasma carotenoids associations may reflect antioxidant effects.