A triterpenoid (corosolic acid) ameliorated AOM-mediated aberrant crypt foci in rats: modulation of Bax/PCNA, antioxidant and inflammatory mechanisms.

Corosolic acid (CA) is a well-known natural pentacyclic triterpene found in numerous therapeutic plants that can exhibit many bioactivities including anti-inflammatory and anti-tumor actions. The current investigation explores the chemoprotective roles of CA against azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Thirty Sprague Dawley rats were grouped in 5 cages; Group A, normal control rats inoculated subcutaneously (sc) with two doses of normal saline and fed orally on 10% tween 20; Groups B-E received two doses (sc) of azoxymethane in two weeks and treated with either 10% tween 20 (group B) or two intraperitoneal injections of 35 mg/kg 5-fluorouracil each week for one month (group C), while group D and E treated with 30 and 60 mg/kg, respectively, for 2 months. The toxicity results showed lack of any behavioral abnormalities or mortality in rats ingested with up-to 500 mg/kg of CA. The present AOM induction caused a significant initiation of ACF characterized by an increased number, larger in size, and well-matured tissue clusters in cancer controls. AOM inoculation created a bizarrely elongated nucleus, and strained cells, and significantly lowered the submucosal glands in colon tissues of cancer controls compared to 5-FU or CA-treated rats. CA treatment led to significant suppression of ACF incidence, which could be mediated by its modulatory effects on the immunohistochemical proteins (pro-apoptotic (Bax) and reduced PCNA protein expressions in colon tissues). Moreover, CA-treated rats had improved oxidative stress-mediated cytotoxicity indicated by increased endogenous antioxidants (SOD and CAT) and reduced lipid peroxidation indicators (MDA). In addition, CA ingestion (30 and 60 mg/kg) suppressed the inflammatory cascades, indicated by decreased serum TNF-α and IL-6 cytokines and increased anti-inflammatory (IL-10) cytokines consequently preventing further tumor development. CA treatment maintained liver and kidney functions in rats exposed to AOM cytotoxicity. CA could be a viable alternative for the treatment of oxidative-related human disorders including ACF.

In silico exploration of PD-L1 binding compounds: Structure-based virtual screening, molecular docking, and MD simulation.

Programmed death-ligand 1 (PD-L1), a transmembrane protein, is associated with the regulation of immune system. It frequently has overexpression in various cancers, allowing tumor cells to avoid immune detection. PD-L1 inhibition has risen as a potential strategy in the field of therapeutic immunology for cancer. In the current study, structure-based virtual screening of drug libraries was conducted and then the screened hits were docked to the active residues of PD-L1 to select the optimal binding poses. The top ten compounds with binding affinities ranging from -10.734 to -10.398 kcal/mol were selected for further analysis. The ADMET analysis of selected compounds showed the compounds meet the criteria of ADMET properties. Further, the conformational changes and binding stability of the top two compounds was analyzed by conducting 200 ns simulation and it was observed that the hits did not exert conformational changes to the protein structure. All the results suggest that the chosen hits can be considered as lead compounds for the inhibition of biological activity of PD-L1 in in vitro studies.

A bitter flavonoid gum from Dorema aucheri accelerate wound healing in rats: Involvement of Bax/HSP 70 and hydroxyprolin mechanisms.

BACKGROUND: Dorema aucheri gum (DAG) is a bitter flavonoid gum widely used for numerous medicinal purposes including wound recovery. The present work investigates the acute toxicity and wound-healing effects of DAG in excisional skin injury in rats. MATERIALS AND METHODS: Sprague Dawley rats (24) were clustered into four groups, each rat had a full-thickness excisional dorsal neck injury (2.00 cm) and addressed with 0.2 mL of the following treatments for 15 days: Group A (vehicle), rats addressed with normal saline; Group B, rats received intrasite gel; C and D, rats addressed with 250 and 500 mg/kg of DAG, respectively. RESULTS: The results revealed the absence of any toxic signs in rats who received oral dosages of 2 and 5 g/kg of DAG. Wound healing was significantly accelerated following DAG treatments indicated by smaller open areas and higher wound contraction percentages compared to vehicle rats. Histological evaluation revealed higher fibroblast formation, collagen deposition, and noticeably lower inflammatory cell infiltration in granulated skin tissues of DAG-addressed rats compared to vehicle rats. DAG treatment caused significant modulation of immunohistochemical proteins (decreased Bax and increased HSP 70) and inflammatory mediators (reduced TNF-α, IL-6, and magnified IL-10), which were significantly varied compared to vehicle rats. Moreover, topical DAG treatment led to significant upregulation of the hydroxyproline (HDX) (collagen) and antioxidant content. At the same time, decreased the lipid peroxidation (MDA) levels in healed tissues obtained from DAG-treated rats. CONCLUSION: The present wound contraction by DAG might be linked with the modulatory effect of its phytochemicals (polysaccharides, flavonoids, and phenolic) on the cellular mechanisms, which justify their folkloric use and provokes further investigation as therapeutic drug additives for wound contraction.

Exploring the Chemical Composition, Antioxidant, and Antibacterial Properties of Helix aspersa Müller Flesh Crude Extract: A Comprehensive Investigation.

Snail flesh is a highly nutritious and easily digestible food commonly integrated into the human diet. In this study, snails belonging to the Helix aspersa Müller species were used to determine their chemical composition and evaluate the antioxidant and antibacterial activities of their flesh using successive maceration extractions with three solvents of different polarities. Biomolecules were analyzed spectrophotometrically, and their chemical compositions were determined by using gas chromatography coupled with mass spectroscopy. The antioxidant activity was assessed using three tests: DPPH, iron-reducing power test, and total antioxidant activity. The ethanol extract was found to be the most effective, with a high yield and high biomolecule content compared with other extracts. The extracts showed a significant amount of antioxidants, ranging from 3.14 to 7.04 mg AAE g-1 of dry matter, according to the total antioxidant activity assay. The DPPH scavenging capacity showed a reduction of the radical, with inhibitory concentrations ranging from 507.07 to 829.49 µg mL-1. In contrast, the iron-reducing power ranged from 67.98 to 424.74 µg mL-1. All of the strains studied responded favorably to the antimicrobial effects of H. aspersa extracts, with a zone of inhibition ranging from 8.48 to 15.53 mm. Additionally, at approximately 15 mg mL-1, the ethanolic extract had the lowest minimum inhibitory concentration against Pseudomonas aeruginosa. H. aspersa Müller flesh is rich in biomolecules with antioxidant and antibacterial activities, which could justify its use as a natural product and in therapeutic applications in the food industry.

The diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure.

AIMS: Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers. METHODS AND RESULTS: RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with versus without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure and cardiovascular mortality.We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data was available for 12, with ERBB3, NRXN3 and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired left ventricular contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles. CONCLUSIONS: DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with left ventricular dysfunction, incident heart failure and cardiovascular mortality.

Effect of Lactiplantibacillus plantarum on the growth, hemato-biochemical, inflammation, apoptosis, oxidative stress markers, involved gens and histopathological alterations in growing rabbits challenged with aflatoxin B1.

Aflatoxin B1 (AFB1) is a significant pollutant found in food and feed, posing a threat to public health. The objective of this study was to assess the effect of Lactiplantibacillus plantarum (LACP) against AFB1 in growing rabbits by investigating growth, serum metabolites, immunity, antioxidant capacity, and inflammatory response. A total of 60 growing male rabbits (721.5 ± 2.68g) were allocated to 4 experimental groups. The control group receiving only a basal diet, the AFB1 group (0.3 mg AFB1/kg diet), the LACP group (1 × 109 cfu/g /kg diet), and the combination group (1 × 109 cfu/g + 0.3 mg AFB1/kg diet; AFB1+ LACP) for 8 wk. The administration of AFB1 alone significantly decreased the final body weight, body gain, and feed intake, while significantly increasing the feed conversion ratio (P < 0.05). A significant decline in total proteins and globulins, along with elevated levels of hepatic enzymes (AST, ALP, ALT, and GGT) and renal function markers (creatinine and uric acid), were observed in the AFB1-contaminated group (P < 0.05). Immunoglobulins (IgG and IgM) were significantly decreased, alongside a significant elevation of triglycerides, direct bilirubin, and indirect bilirubin in growing rabbits fed diets with AFB1 (P < 0.05). Supplementing the AFB1 diet with LACP restored the growth reduction, improved liver (AST, ALP, ALT, and GGT) and kidney (creatinine and uric acid) functions, and enhanced immune markers in rabbit serum (P < 0.05). Antioxidant indices (SOD, GSH, and CAT) were significantly decreased in the AFB1 group (P < 0.05). However, the addition of LACP to the AFB1-contaminated diets improved antioxidant capacity and malondialdehyde (MDA) and protein carbonylation (PC) in hepatic tissues of rabbits (P < 0.05). Serum interlukin-4 (IL-4) and interferon gamma (IFN-γ) levels were significantly increased in the AFB1 group (P < 0.05), but the addition of LACP significantly reversed this elevation. AFB1 downregulated the expression of immune-inflammatory genes such Nrf2, IL-10, and BCL-2 genes, while up-regulating the caspase-3 (CASP3) gene (P < 0.05). Supplementing AFB1 diet with LACP significantly decreased the expression of immune-inflammatory genes (Nrf2, IL-10, and BCL-2) and reduced the expression of the apoptotic-related gene CASP3. This study highlights the potential of L. plantarum (1 × 109 cfu/g /kg diet) as a protective agent against AFB1 in growing rabbits by enhancing antioxidant and immune function and reducing apoptosis and inflammation pathways.

Atherosclerotic Cardiovascular Disease Novel and Traditional Risk Factors in Middle Eastern Young Women. The ANCORS-YW Study.

Background: There is paucity of data on the prevalence of novel and traditional cardiovascular risk factors in young women with atherosclerotic cardiovascular disease (ASCVD) in the Middle East. We sought to evaluate clinical profiles and prevalence of novel and traditional risk factors in Middle Eastern young women with ASCVD compared with age-matched controls. Methods: Women 18-50 years of age who have ASCVD were enrolled and each was aged-matched with two women with no ASCVD. Prevalence of novel and traditional risk factors was compared in the two groups. Multivariable analyzes examined the independent association of 16 factors with ASCVD. Results: Of 627 young women enrolled mean age 44.1 ± 5.2 years; 209 had ASCVD and 418 served as controls. Women with ASCVD had significantly higher prevalence of five of the studied traditional risk factors (hypertension, type 2 diabetes [T2D], smoking, low-density lipoprotein cholesterol serum levels, and family history of premature ASCVD [FHx]) than women with no ASCVD. Additionally, of the 11 novel and psychosocial risk factors studied, four showed significantly higher prevalence in young women with ASCVD (preterm delivery, hypertensive disease of pregnancy gestational diabetes, and low level of education). Multivariable analyzes showed hypertension, T2D, smoking, FHx, persistent weight gain after pregnancy and low level of education were independently associated with ASCVD. Conclusions: In this study of young Middle Eastern women; traditional risk factors as well as persistent weight gain after pregnancy were more prevalent in women with ASCVD compared with controls.The study is registered with ClinicalTrials.gov, unique identifier number NCT04975503.

The relationship between quality of life, sleep quality, mental health, and physical activity in an international sample of college students: a structural equation modeling approach.

Objective: We assessed the direct and indirect relationships between sleep quality, mental health, and physical activity with quality of life (QOL) in college and university students. Methods: In a cross-sectional design, 3,380 college students (60% females; age = 22.7 ± 5.4) from four continents (Africa: 32%; America: 5%; Asia: 46%; and Europe: 15%; others: 2%) completed the Pittsburgh Sleep Quality Index (PSQI); Insomnia Severity Index (ISI); Epworth Sleepiness Scale (ESS); the Depression, Anxiety, and Stress Scale 21 (DASS); the International Physical Activity Questionnaire short-form (IPAQ); and the World Health Organization Quality of Life-BREF (WHOQOL-Brief). Results: We showed that sleep quality, insomnia, and depression had direct negative effects on the physical domain of QOL (ß = -0.22, -0.19, -0.31, respectively, p < 0.001). There was a strong negative direct association between depression and the psychological domain of QOL (ß = -0.60, z = -22.21, p < 0.001). Both stress and PSQI had direct effects on social relationships QOL (ß = 0.11; z = 4.09; and ß = -0.13; z = -7.40, respectively, p < 0.001). However, depression had the strongest direct impact on social relationships QOL (ß = -0.41, z = -15.79, p < 0.001). Conclusion: The overall QOL of university students is associated with their sleep quality, mental health, and physical activity warranting further interventional studies aiming at improving students' quality of life.

Optimizing the Extraction Efficiency of Flaxseed Gum Using a Response Surface Methodology Approach.

The extraction of gum from natural raw materials is of increasing importance in various industries, including food, pharmaceuticals, and cosmetics, particularly due to their emulsifying properties and potential applications as stabilizers and thickeners. This study presents an insight on the influence of changing parameters like reagents and operating condition on yield and some properties of the flax (Linum usitatissimum L.) seed gum. The extraction conditions were meticulously examined using a full factorial design, highlighting the significant impact of pretreatment, seed preparation, and solvent selection on the extraction yield. A response surface methodology (RSM) was then applied to optimize the water/benzoic acid ratio of the pretreatment step, the ethyl alcohol/water ratio, and the medium pH of the extraction method, resulting in a maximum yield of 14.47%. Furthermore, detailed analyses of the chemical and emulsifying properties of the gum were conducted showing emulsifying capacities over 94%, offering promising application prospects, particularly in the food industry.

The chemical composition and the preservative, antimicrobial, and antioxidant effects of Thymus broussonetii Boiss. essential oil: an in vitro and in silico approach.

Introduction: The aim of this study was to evaluate the antioxidant, antimicrobial, and preservative efficacy of Thymus broussonetii Boiss. essential oil (EO) in a topically applied formulation using a challenge test. Methods: The essential oil was extracted from the aerial part of T. broussonetii using hydrodistillation, and the obtained EO was further analyzed by gas chromatography/mass spectrometry (GC/MS). The antioxidant effect of the EO was evaluated using three methods: the inhibition of free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH), ß-carotene-linoleic acid, and the ferric reducing antioxidant power (FRAP) methods. The antimicrobial activity and the minimum inhibitory concentration (MIC) of this EO were assayed by the disk-diffusion method and the broth microdilution method, respectively. The preservative efficacy of T. broussonetii EO was assayed at 1% and 2% (v/w) in a topical cream formulation using a challenge test against standard-specific microorganisms recommended by the European Pharmacopoeia. Furthermore, the identified phytochemical compounds were docked for their effect on nicotinamide adenine dinucleotide phosphate oxidase, human casein kinase 1 alpha 1 (CSNK1A1), glycogen synthase kinase 3, Staphylococcus aureus nucleoside diphosphate kinase, Escherichia coli beta-ketoacyl-[acyl-carrier protein] synthase, Pseudomonas aeruginosa LasR ligand-binding domain, and sterol 14-alpha demethylase (CYP51) from Candida albicans. The ADME/toxicity was predicted by analyzing the absorption, distribution, metabolism, and excretion parameters. Results and discussion: chemical composition of the EO revealed the presence of thymol (63.09%), p-cymene (11%), and γ-terpinene (8.99%) as the major components. The antioxidant assays revealed that the essential oil exhibited strong antioxidant activity, as indicated by the minimum inhibitory concentration IC50 (IC50 = 210 ± 0.3 µg/mL for the DPPH assay, IC50 = 145 ± 0.1 µg/mL for the ß-carotene assay, and IC50 = 84 ± 0.21 µg/mL for the FRAP assay) when compared to quercetin and butylated hydroxytoluene (BHT) as controls. The investigated essential oil exhibited important antimicrobial activity against all the tested microorganisms, and the MICs of the EO against bacteria and fungi were 0.02%-1%. Moreover, the EO of T. broussonetii evaluated at 2% (v/w) in a cream formulation succeeded in satisfying the A criteria for preservation efficacy against S. aureus, E. coli, and Aspergillus brasiliensis but exhibited less efficacy against P. aeruginosa (1.78 log reduction in the number of CFU/g after 7 days of evaluation) and C. albicans (1.09 log reduction in the number of CFU/g after 14 days of evaluation) when compared to the synthetic preservative phenoxyethanol 1% (v/w). In silico results showed that the antimicrobial activity of T. broussonetii EO is mostly attributed to thymol, terpinen-4-ol, and aromadendrene, while the antioxidant activity is attributed to thymol. These results indicate that the EO of T. broussonetii possesses important antimicrobial and antioxidant properties and can, therefore, be used as a natural preservative ingredient in the cosmetic industry.

Physicochemical Characterization of Moroccan Honey Varieties from the Fez-Meknes Region and Their Antioxidant and Antibacterial Properties.

Honey, with its varied and extensive characteristics, is a complex and diverse biological substance that has been used since ancient times. The aim of this study is to thoroughly characterize the physicochemical, phytochemical, and biological properties of four floral honey varieties from the Fez-Meknes region in Morocco, with the goal of promoting the valorization of Moroccan honey in skincare and cosmetic products. The analyses of their physicochemical characteristics encompass various parameters such as pH, acidity, density, water content, Brix index, conductivity, ash content, hydroxymethylfurfural (HMF) content, and color. The levels of polyphenols range from 22.1 ± 0.4 to 69.3 ± 0.17 mg GAE/100 g of honey, measured using the Folin-Ciocalteu method for polyphenol quantification. Additionally, the estimation of flavonoid quantities in 100 g of honey, conducted using the aluminum trichloride method, reveals values ranging from 3.6 ± 0.2 to 7.2 ± 0.6 mg QE. Furthermore, it is noteworthy that honey exhibits high levels of glucose and relatively low concentrations of proteins. The quantitative evaluation of antioxidant effects, carried out through the 2,2-diphenyl-1-picrylhydrazyl free-radical-scavenging method and the ferric-reducing antioxidant power (FRAP) method, highlights the strong antioxidant capacity of multifloral honey, characterized by low inhibitory concentration values (IC50 = 30.43 mg/mL and EC50 = 16.06 mg/mL). Moreover, all honey varieties demonstrate antibacterial and antifungal properties, with multifloral honey standing out for its particularly pronounced antimicrobial activity. The correlation analyses between phytochemical composition and antioxidant and antibacterial activities reveal an inverse relationship between polyphenols and IC50 (DPPH) and EC50 (FRAP) concentrations of honey. The correlation coefficients are established at R2 = -0.97 and R2 = -0.99, respectively. Additionally, a significant negative correlation is observed between polyphenols, flavonoids, and antifungal power (R2 = -0.95 and R2 = -0.96). In parallel, a marked positive correlation is highlighted between antifungal efficacy, DPPH antioxidant activity (R2 = 0.95), and FRAP (R2 = 0.92). These results underscore the crucial importance of phytochemical components in the beneficial properties of honey, meeting international quality standards. Consequently, honey could serve as a natural alternative to synthetic additives.

Wood calamint ameliorates ethanol-induced stomach injury in rats by augmentation of hsp/bax and inflammatory mechanisms.

Clinopodium menthifolium (wood calamint) is a folkloric medicinal plant ingested as a treatment for many human disorders including gastric disorders. Our study evaluates the anti-ulcer potentials of Clinopodium menthifolium ethanol extracts (CMEE) in induced gastric ulcers in rats. Thirty Dawley male rats were divided into 5 groups: normal and ulcer controls, treated orally with Tween 20%; reference rats treated with Omeprazole 20 mg/kg, and the remaining two groups received 250 and 500 mg/kg CMEE for 2 weeks. After that, food was taken away for 24 h, and then, rats received ethanol-induced gastric ulceration (except normal control), 80% (1 ml/rat). After anesthetization and sacrificing, the ulcer index, mucus content, and other ulcer measurements were obtained from dissected rat stomachs. Stomach tissues were also analyzed by different histology procedures and homogenized stomach tissues were assessed for their antioxidant contents. The toxicity trial showed the absence of any toxic signs in rats supplemented with 2 and 5 g/kg of CMEE. The gastroprotective results showed a significantly lower ulcer index and higher gastric mucin content in CMEE-ingested rats compared to ulcer controls. Furthermore, CMEE treatments significantly increased the intensity of periodic acid Schiff stained (PAS), HSP 70 protein, and down-regulation of Bax protein expression in the stomach epithelium. Rats supplemented with 500 mg/kg revealed noticeable changes in their serum inflammatory cytokines along with positive regulations of antioxidant enzymes. The outcomes provide a scientific backup behind the gastroprotective potential effect of CMEE that could serve as a natural resource against peptic ulcers.

Cumin (Cuminum cyminum L.) seeds accelerates wound healing in rats: Possible molecular mechanisms.

Wound healing is a complex, intricate, and dynamic process that requires effective therapeutic management. The current study evaluates the wound healing potentials of methanolic extract of Cuminum cyminum L. seeds (CCS) in rats. Sprague Dawley (24) rats were distributed into four cages, wounds produced on the back of the neck, and received two daily topical treatments for 14 days: A, rats received normal saline; B, wounded rats treated with intrasite gel; C and D, rats received 0.2 mL of 250 and 500 mg/kg of CCS, respectively. After that, wound area and closure percentage were evaluated, and wound tissues were dissected for histopathological, immunohistochemical, and biochemical examinations. Acute toxicity trials of methanolic extract of CCS showed the absence of any physiological changes or mortality in rats. CCS application caused a significant reduction in wound size and a statistically elevated percentage of wound contraction than those of vehicle rats. CCS treatment caused significant up-regulation of collagen fiber, fibroblasts, and fewer inflammatory cells (inflammation) in granulation tissues. TGF-ß1 (angiogenetic factor) was significantly more expressed in CCS-treated rats in comparison to normal saline-treated rats; therefore, more fibroblasts transformed into myofibroblasts (angiogenesis). CCS-treated rats showed remarkable antioxidant potentials (higher SOD and CAT enzymes) and decreased MDA (lipid peroxidation) levels in their wound tissue homogenates. Hydroxyproline amino acid (collagen) was significantly up-regulated by CCS treatment, which is commonly related to faster wound closure area. The outcomes suggest CCS as a viable new source of pharmaceuticals for wound treatment.

P2Y12 Inhibition in Patients Requiring Oral Anticoagulation After Percutaneous Coronary Intervention: The SWAP-AC-2 Study.

BACKGROUND: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (ie, known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel. OBJECTIVES: The authors sought to assess the pharmacodynamic (PD) effects of clopidogrel vs low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score. METHODS: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n = 39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n = 20; 60 mg twice a day) or clopidogrel (n = 19; 75 mg once a day). Patients with an ABCD-GENE score <10 (n = 42) were treated with clopidogrel (75 mg once a day; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y12 signaling (VerifyNow P2Y12 reaction units [PRU], light transmittance aggregometry, and vasodilator-stimulated phosphoprotein); makers of thrombosis not specific to P2Y12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days. RESULTS: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [Q1-Q3: 3.0-46.0] vs 154.5 [Q1-Q3: 77.5-183.0]; P < 0.001) and peak (6.0 [Q1-Q3: 4.0-14.0] vs 129.0 [Q1-Q3: 66.0-171.0]; P < 0.001). Trough PRU levels in the control arm (104.0 [Q1-Q3: 35.0-167.0]) were higher than ticagrelor-based DAT (P = 0.005) and numerically lower than clopidogrel-based DAT (P = 0.234). Results were consistent by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. Markers measuring other pathways leading to thrombus formation were largely unaffected. CONCLUSIONS: In NOAC-treated patients undergoing PCI with an ABCD-GENE score ≥10, ticagrelor-based DAT using a 60-mg, twice-a-day regimen reduced platelet P2Y12 reactivity compared with clopidogrel-based DAT. (Tailoring P2Y12 Inhibiting Therapy in Patients Requiring Oral Anticoagulation After PCI [SWAP-AC-2]; NCT04483583).

Continuous glucose monitoring for the routine care of type 2 diabetes mellitus.

Although continuous glucose monitoring (CGM) devices are now considered the standard of care for people with type 1 diabetes mellitus, the uptake among people with type 2 diabetes mellitus (T2DM) has been slower and is focused on those receiving intensive insulin therapy. However, increasing evidence now supports the inclusion of CGM in the routine care of people with T2DM who are on basal insulin-only regimens or are managed with other medications. Expanding CGM to these groups could minimize hypoglycaemia while allowing efficient adaptation and escalation of therapies. Increasing evidence from randomized controlled trials and observational studies indicates that CGM is of clinical value in people with T2DM on non-intensive treatment regimens. If further studies confirm this finding, CGM could soon become a part of routine care for T2DM. In this Perspective we explore the potential benefits of widening the application of CGM in T2DM, along with the challenges that must be overcome for the evidence-based benefits of this technology to be delivered for all people with T2DM.

Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

AIM: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. RESULTS: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1ß, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1ß, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1ß (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. CONCLUSIONS: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. TRIAL REGISTRATION: The trial was prospectively registered (ISRCTN13641847).

Identifying Predictors of Neck Disability in Patients with Cervical Pain Using Machine Learning Algorithms: A Cross-Sectional Correlational Study.

(1) Background: Neck pain intensity, psychosocial factors, and physical function have been identified as potential predictors of neck disability. Machine learning algorithms have shown promise in classifying patients based on their neck disability status. So, the current study was conducted to identify predictors of neck disability in patients with neck pain based on clinical findings using machine learning algorithms. (2) Methods: Ninety participants with chronic neck pain took part in the study. Demographic characteristics in addition to neck pain intensity, the neck disability index, cervical spine contour, and surface electromyographic characteristics of the axioscapular muscles were measured. Participants were categorised into high disability and low disability groups based on the median value (22.2) of their neck disability index scores. Several regression and classification machine learning models were trained and assessed using a 10-fold cross-validation method; also, MANCOVA was used to compare between the two groups. (3) Results: The multilayer perceptron (MLP) revealed the highest adjusted R2 of 0.768, while linear discriminate analysis showed the highest receiver characteristic operator (ROC) area under the curve of 0.91. Pain intensity was the most important feature in both models with the highest effect size of 0.568 with p < 0.001. (4) Conclusions: The study findings provide valuable insights into pain as the most important predictor of neck disability in patients with cervical pain. Tailoring interventions based on pain can improve patient outcomes and potentially prevent or reduce neck disability.

Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses.

The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules.

Using artificial intelligence for exercise prescription in personalised health promotion: A critical evaluation of OpenAI's GPT-4 model.

The rise of artificial intelligence (AI) applications in healthcare provides new possibilities for personalized health management. AI-based fitness applications are becoming more common, facilitating the opportunity for individualised exercise prescription. However, the use of AI carries the risk of inadequate expert supervision, and the efficacy and validity of such applications have not been thoroughly investigated, particularly in the context of diverse health conditions. The aim of the study was to critically assess the efficacy of exercise prescriptions generated by OpenAI's Generative Pre-Trained Transformer 4 (GPT-4) model for five example patient profiles with diverse health conditions and fitness goals. Our focus was to assess the model's ability to generate exercise prescriptions based on a singular, initial interaction, akin to a typical user experience. The evaluation was conducted by leading experts in the field of exercise prescription. Five distinct scenarios were formulated, each representing a hypothetical individual with a specific health condition and fitness objective. Upon receiving details of each individual, the GPT-4 model was tasked with generating a 30-day exercise program. These AI-derived exercise programs were subsequently subjected to a thorough evaluation by experts in exercise prescription. The evaluation encompassed adherence to established principles of frequency, intensity, time, and exercise type; integration of perceived exertion levels; consideration for medication intake and the respective medical condition; and the extent of program individualization tailored to each hypothetical profile. The AI model could create general safety-conscious exercise programs for various scenarios. However, the AI-generated exercise prescriptions lacked precision in addressing individual health conditions and goals, often prioritizing excessive safety over the effectiveness of training. The AI-based approach aimed to ensure patient improvement through gradual increases in training load and intensity, but the model's potential to fine-tune its recommendations through ongoing interaction was not fully satisfying. AI technologies, in their current state, can serve as supplemental tools in exercise prescription, particularly in enhancing accessibility for individuals unable to access, often costly, professional advice. However, AI technologies are not yet recommended as a substitute for personalized, progressive, and health condition-specific prescriptions provided by healthcare and fitness professionals. Further research is needed to explore more interactive use of AI models and integration of real-time physiological feedback.