Correction to "Topical Probiotic Therapy Reduces Chemotherapy-Induced Oral Mucositis: Preclinical Evaluation in a Rat Model".

Oral mucositis (OM) is a debilitating complication of chemotherapy and radiotherapy, characterized by painful ulcerations and inflammation of the oral mucosa. Current treatments provide limited efficacy and often lack regenerative properties. This study aimed to evaluate the therapeutic potential of topically administered probiotics in a rat model of OM. OM was induced in Sprague-Dawley rats using 5-fluorouracil (5-FU) and acetic acid. Rats were randomized into groups receiving topical formulations of Lactobacillus acidophilus, Lactobacillus reuteri, Bacillus clausii, Bacillus coagulans, Lactobacillus plantarum, sucralfate, triamcinolone, and control. Treatments were applied for 5 consecutive days. OM severity was assessed using macroscopic and histopathological scoring, fibrosis grading, and inflammatory markers (TNF-α, IL-10, PGE2). L. acidophilus and L. reuteri significantly reduced macroscopic and histopathological OM scores compared to controls. L. acidophilus also demonstrated a notable reduction in fibrosis and PGE2 levels (p < 0.05), suggesting anti-inflammatory and antifibrotic activity. B. clausii and B. coagulans showed moderate efficacy, while sucralfate and triamcinolone reduced mucosal inflammation but were less effective in tissue regeneration. No significant changes in IL-10 were observed across groups. Topically applied probiotics, particularly L. acidophilus, exhibit significant therapeutic potential in attenuating chemotherapy-induced OM by modulating inflammation and promoting mucosal healing. These findings support further exploration of localized probiotic therapies as a novel, non-systemic approach to manage OM in clinical settings.

Background/Introduction Positron emission tomography (PET) is now an established method for myocardial perfusion imaging (MPI). The available tracers show a number of limitations, therefore the 18F-labelled tracer is in high demand now. Purpose The preclinical studies aimed to characterise [18F]SYN2 (18F acridinium derivative) on animal model to prove it can be used as a novel MPI radiotracer for PET. Methods The preclinical evaluation was conducted on Wistar rats. The utility of [18F]SYN2 as heart-targeted tracer was tested by 45-min dynamic microPET imaging. The physiological distribution and pharmacokinetics were examined on ex vivo tissue/organs radioactivity measurement at 0.25, 0.5, 1, 2, 3 and 6 h. The obtained data was extrapolated to humans using the simplest allometric scaling model. The effective dose was calculated using OLINDA/EXM® software. The pharmacokinetics in plasma (at 4, 15, 30, 60 min, 4, and 24 h) and potential toxicity studies (at 24 hour and 14 day) were evaluated after a bolus i.v. administration of 2 mg/kg of SYN2 (the non-radioactive standard). The pharmacodynamics was assessed in vitro in radioligand binding assays for 68 targets. The tracer metabolism was studied by the SYN2 incubation in rat, dog and human hepatocytes for 60 min. All animal procedures were conducted according to the European and National Legislation. Results The microPET images showed rapid, high and stable myocardial [18F]SYN2 uptake with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02 %ID/g at 15 min and 2.79 %ID/g at 6 h). The uptake in the liver was relatively low (max. 0.89 %ID/g at 15 min), while in the lungs was much higher and decreased rapidly over time (from 3.04 %ID/g at 15 min to 0.55 %ID/g at 6 h). The study showed that the radiotracer was eliminated predominantly by biliary excretion. The estimated effective dose for human was 0.0109 mSv/MBq. SYN2 showed rapid plasma clearance within 1 hour post injection (2.59 L/h/kg) with elimination half-life of 0.26 h. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL). Radioligand binding assays showed significant responses in 3/68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule. Conclusion [18F]SYN2 showed favourable pharmacokinetic and pharmacodynamic profile in the rat model. The tracer, with its rapid plasma clearance, high and stable uptake in the myocardium allowed clear visualization of the heart in microPET. [18F]SYN2 was well-tolerated and showed moderate radiation exposure. Encouraging results of preclinical evaluation merit further exploration in clinical studies.MicroPET images of [18F]SYN2

BackgroundChronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.Methods and findingsTo establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow.Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population.ConclusionsOur mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.Trial registrationClinicalTrials.gov NCT01640964

This study aimed to develop a reliable chemotherapy-induced oral mucositis (CIOM) rat model by intraperitoneally administering a single dosage of 5-fluorouracil (5-FU) combined with a chemical stimulus. The 5-FU dosage for CIOM development was determined by the survival rate of rats administrated 160 mg/kg, 200 mg/kg, and 240 mg/kg of 5-FU. Thirty rats were assigned to normal control (NC) and three experimental groups: i) ulcer formation without 5-FU administration (PBS/U+), ii) 5-FU administration without ulcer formation (5-FU/U-), and iii) ulcer formation after 5-FU administration (5-FU/U+). White blood cell count and weight were measured at the day of 5-FU administration (D0), ulcer formation (D2), and two days after ulcer formation (D4). The oral mucosa for histologic evaluations was obtained two (D4) and five days (D7) after ulcer formation. The 5-FU dosage for CIOM development was 200 mg/kg. White blood cell count (WBC) counts and weight of rats were significantly lower in 5-FU/U- (WBC, p<0.001; weight, p=0.002) and 5-FU/U+ (WBC, p<0.001; weight, p<0.001) groups compared to those in the NC group at D4. The number of Ki-67 positive cells in the oral epithelium was lower in 5-FU/U+ group compared to that in NC (p<0.001) and PBS/U+ (p=0.047) groups at D7. Single administration of 200 mg/kg of 5-FU combined with a chemical stimulus can lead to an immune-suppressive status, failure of weight gain, and impairment of epithelium regeneration as observed in a CIOM rat model.

Assessment of the preventive activity of Pinus brutia Ten. (Pinaceae) against in vivo acute lung injury model

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Electromagnetic spectrum of the UV region predominantly becomes the reason for skin's detrimental effects that give the genesis of innumerable skin ailments; because of this reason, the sunscreen products are required before condition in day to day lifestyle; products such as moisturizers, lotions, creams, shampoos, and other hair and skin preparations are accessible and accompanied by sunscreen properties, but they do not provide extended effect, also causes side effects due to harsh chemicals. The present study focuses on the effects of polyherbal extracts containing Microsponge gel for the protection of skin from ultraviolet rays. In the present research, already prepared Microsponge gel through quasi-emulsion solvent diffusion (QESD) technique was used for the HPLC, in-silico, in-vitro antioxidant activity, and in-vivo study. AdmetSAR software tool was utilized for the in-silico study, whereas for the in-vivo study, UV radiations are given on Albino rats using solarimeter. Results shown the active constituents are non-carcinogenic and non-toxic; IC50 values show good antioxidant activity and minimal effect of UV radiations after application of the gel formulation on animal skin. The results manifest prominent effects on animal skin further test for presence of ascorbic acid level and total protein in blood further verify the efficacy of the formulation. The study consequently established a strong ground for further extensive clinical studies.

Aim was to develop and optimize multiunit gastro-retentive floating beads (FBs) intended for localized and prolonged release of ginger for treating gastric ulcers. Protective effect of ginger extract (GE) against ulcer is well documented, but therapeutic use is compromised due to poor bioavailability and physicochemical properties. GE was only slightly soluble (3.19 ± 0.38 mg/ml) in simulated gastric fluid (SGF; pH 1.2). The solubility decreased in water to 0.69 ± 0.03 mg/ml and further by 26% in the presence of calcium carbonate (0.5% w/v). We prepared FBs of GE using calcium carbonate and sodium alginate in different proportions. Beads were evaluated for diameter, buoyancy, entrapment, and porosity. In vitro dissolution showed a Fickian release with a cumulative release of >80% at 24 h. Preclinical evaluation was done in cold-restraint stress induced gastric ulcers, in albino rats, in terms of (i) ulcer index, hemorrhagic streaks (l), mucus content, (ii) oxido-nitrosative stress, and (iii) histopathology. GE loaded FBs (200 mg/kg) were significantly better than free GE and better/equivalent to cimetidine (10 mg/kg). The system was evaluated for therapeutic effect (curative), i.e. after the induction of ulcers. Most of the natural phytochemical or antioxidants show pretreatment effectiveness. We, however, developed and established GE FBs for sustained curative effect.

Patent Blue V (PBV), a dye used clinically for sentinel lymph node detection, was mixed with human serum albumin (HSA). After binding to HSA, the fluorescence quantum yield increased from 5 × 10−4 to 1.7 × 10−2, which was enough to allow fluorescence detection and imaging of its distribution. A detection threshold, evaluated in scattering test objects, lower than 2.5 nmol × L−1 was obtained, using a single-probe setup with a 5-mW incident light power. The detection sensitivity using a fluorescence imaging device was in the µmol × L−1 range, with a noncooled CCD camera. Preclinical evaluation was performed on a rat model and permitted to observe inflamed nodes on all animals.

Cleome gynandra, a kind of medicinal herb which has strong antioxidant properties has been traditionally used for treating various ailments including skin inflammatory diseases. To date, the anti-inflammatory efficacy of C. gynandra based cream has not been reported. The aim of the study was to evaluate the anti-inflammatory activities of C. gynandra leaf extract cream using an in vivo arachidonic acid-induced ear edema in the rat model. The expression of genes related to rat ear inflammation was measured to evaluate the topical anti-inflammatory activity of C. gynandra cream. The toxicity effect of C. gynandra cream was determined through a skin irritation test in rats and human cumulative skin irritation assessment. Data collected evidently showed a significantly higher (p&lt;0.05) percentage of recovery rate (70.21±5.14%) in rats treated with C. gynandra cream when compared to the negative control (27.43±4.75%) and basal cream (55.8±4.61%), indicating that C. gynandra cream effectively reduced inflammation symptoms in rat ear edema model study. The expressions of all pro-inflammatory cytokines and acute inflammatory-related genes were significantly down-regulated in C. gynandra cream-treated group than untreated group (negative control). The dermatological safety aspect of C. gynandra cream was confirmed by human cumulative skin irritation assessment with the average cumulative irritation index of 0.046, indicating a non-irritating effect. The overall findings demonstrated that C. gynandra cream has great potential to be applied for treating skin-related inflammatory diseases.

Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303. Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3. Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 μM, compared to 1.2-2.5 μM for triple negative breast cancer cells, and ~12 μM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.

Deproteinized bovine bone minerals (DBBMs) are effective for bone regeneration. However, their limited plasticity can hinder extensive bone defects treatment. This study aimed to develop a composite bone grafting material that is easy to deploy surgically and promotes robust bone regeneration. DBBM particles were mixed with a clinical-grade gelatin-based hemostatic gel (w/v ratio of 2/3) to create a composite material referred to as synthetic sticky bone (SSB). Structural properties were assessed using confocal laser scanning microscopy and scanning electron microscopy. To evaluate bone regenerative capacity, 20 male Sprague Dawley rats (eight to ten weeks old) with critical-size jawbone defects were treated with SSB, DBBM, or gelatin gel alone, with an empty defect as a control. Samples were collected at two and four weeks for microcomputed tomography (μCT) analysis of bone volume/total tissue volume (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. N), and trabecular separation (Tb. Sp). Histological analyses were conducted to examine material remnants and bone formation. SSB showed a binary paste-like composite property with enhanced injectability and plasticity. μCT and histological assessments confirmed that the SSB-treated group had significantly greater new bone formation compared to the DBBM-treated group after four weeks. SSB, which is a paste-like composite of DBBM particles, and a clinical-grade gelatin-based hemostatic gel demonstrated improved structural plasticity and enhanced bone regeneration, offering a promising solution for treating extensive irregular bone defects.

BackgroundThe neonatal Fc receptor (FcRn) is the key homeostatic regulator of serum albumin (ALB) and IgG by salvage and recycling them in a pH-dependent way. It has been demonstrated that...

BackgroundIncontinence‐associated dermatitis (IAD) is a tough problem in clinical settings, not only increasing the risk of complications like catheter‐related urinary tract infections and pressure ulcers in elderly and critically ill patients, but also prolonging hospital stays, raising hospital costs, and possibly leading to medical disputes. This study is aimed to evaluate the therapeutic effect of silicone dressing combined with topical oxygen therapy on IAD in a rat model.MethodsAn IAD rat model induced by synthetic urine with trypsin was established. Hematoxylin & eosin staining was carried out to examine skin histology. Using immunofluorescence, the microvessel density in the affected skin tissues was determined. ELISA was performed to measure the concentrations of inflammatory cytokines and angiogenic factors in serum. The mRNA expression of EGF, PDGF, and VEGF was detected via qRT‐PCR. Western blotting was employed to determine NF‐κB p65/STAT1 pathway‐related protein levels.ResultsCompared to single therapy, silicone dressing combined with topical oxygen therapy could significantly reduce the severity of IAD, improve skin histology, inhibit inflammation, and promote angiogenesis in IAD rat models. Additionally, the results showed that relatively speaking, the combined therapy suppressed the NF‐κB p65/STAT1 signaling pathway more effectively.ConclusionThese findings indicated that silicone dressing combined with topical oxygen therapy can alleviate IAD through promoting wound healing and inhibiting inflammation via NF‐κB p65/STAT1 signaling pathway in a rat model, which provided a theoretical basis for the prevention and treatment of IAD in clinic.

Use of Cefazolin Microspheres to Treat Localized Methicillin-Resistant Staphylococcus aureus Infections in Rats