Search

This study investigated the effect of oral and topical sodium bicarbonate (SB) on soccer-specific performance during simulated soccer exercise. In a block randomized, double-blind, crossover design, 10 collegiate male soccer players (stature: 181.7 ± 3.2 cm, body mass: 81.7 ± 10.5 kg) performed soccer-specific performance tests (countermovement jumps, Illinois agility, 8 × 25 m repeated sprints) throughout a 90-min soccer-specific aerobic field test (SAFT90) following 0.3 g/kg body mass SB in capsules (SB-ORAL), 0.9036 g/kg body mass PR Lotion (SB-LOTION), or placebo capsules and lotion (PLA). Soccer-specific performance tests were conducted pre-SAFT90, during half-time and post-SAFT90. Blood samples were analyzed for acid–base balance (pH; bicarbonate, HCO 3 − ) and strong ions (sodium, Na+; potassium, K+). Average sprint times were quicker for SB-ORAL than PLA during half-time (3.7%; p =.049; g =.57) and post-SAFT90 (4.9%; p =.041; g =.66). SB-ORAL increased pH and HCO 3 − prewarm-up and during half-time (p <.05), and lowered K+ during half-time (p =.035) compared with PLA. SB-LOTION increased pH (p =.019) and lowered K+ (p =.012) during half-time compared with PLA. SB-LOTION increased Na+ postexercise compared with PLA (p =.008). Repeated sprint times during simulated soccer exercise improved for SB-ORAL, which might have been mechanistically underpinned by elevated blood buffering capacity and greater regulation of strong ion concentration. Consuming SB in capsules is a more effective strategy than topical SB application for improving blood buffering capacity and repeated sprint performance throughout competitive soccer matches. [ABSTRACT FROM AUTHOR]

Caffeine is an ergogenic substance that is consumed globally in many forms. The use of buccally absorbable formulations instead of gastrointestinal uptake has become increasingly popular over the years, especially when accelerated absorption with minimal gastrointestinal stress is desired. This study investigated the impact of five different formulations and administration routes of caffeine on the whole blood concentrations of caffeine, paraxanthine, and theobromine: caffeinated capsules, tablets, shots, pouches, and chewing gums. A uniform dose of caffeine (200 mg) was administered to 16 healthy recreational athletes (26.0 ± 2.1 years) using a randomized crossover design. Samples were taken in the form of dried blood spots at 16 different time points in a 2-hr timeframe after drug administration. The samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method. The results for caffeine showed no significant differences in the overall bioavailability (area under the concentration–time curve), maximal concentration, and time to maximum concentration. However, when analyzing the bioavailability of caffeine in the first 5, 10, and 15 min, the liquid caffeine formulation was superior to other administered forms (p <.05). This indicates that caffeine solubility has a major influence on its absorption rate. In sports, the rate of caffeine absorption must be considered, not only when ingesting anhydrous caffeine, but also when choosing buccal absorption. These findings imply that general guidelines for ergogenic caffeine use should consider the formulation used and, accordingly, the corresponding route of absorption. [ABSTRACT FROM AUTHOR]

Objectives: Sedation is commonly utilized for individuals otherwise unable to receive dental treatment, such as those with disabilities, medically complex conditions, and dentophobics. The aim was to characterize the profiles of patients receiving various types of sedation and assess the corresponding success rates. Method and materials: This was a 5-year records-based retrospective study. Data regarding the indication for sedation, medical history, sedation type, and treatments performed were recorded. Results: In total, 103 patients underwent 389 treatment sessions under sedation; 42.7% of the patients were disabled. The most commonly administered sedation was moderate sedation, (49.4%), followed by deep (36.8%) and inhaled sedation (13.9%). Successful treatment results were achieved in 96.1% of sessions, with no adverse effects noted during recovery. The high success rates were independent of patient age, sex, and sedation type. There was a positive association between the indication for sedation and the type of sedation. The medically complex patients and the dentophobic patients received mainly moderate sedation (85.3% and 58.2%, respectively), whereas the disabled patients received deep sedation (51.2%). In total, 94% of patients were returning (revisiting) patients. A statistically significant association was found between the type of sedation administered and the success rate during the first and last sessions (P< .001). The success rate at the first session may be predictive of the success in subsequent sessions. Conclusion: A significant positive correlation was found between patient characteristics and the chosen sedation type leading to a high success rate across the various sedation modalities. [ABSTRACT FROM AUTHOR]

Purpose: To examine the clinical efficacy of a chlorhexidine gargle combined with recombinant bovine basic fibroblast growth factor (rb-bFGF) gel in the treatment of recurrent oral ulcers and its effects on inflammatory factors, immune function, and recurrence rate. Materials and Methods: Ninety-six patients with recurrent oral ulcers were randomly assigned to two groups: experimental (treatment with chlorhexidine gargle plus rb-bFGF gel) and control (treatment with chlorhexidine gargle alone) (n = 48 cases). The therapeutic efficacy, clinical improvement of symptoms, and recurrence rate within 3 months were compared between the two groups. Serum inflammatory factor and immune factor levels of patients in the two groups were measured before and after treatment. Results: A statistically significantly higher total effective rate was found in patients of the experimental group (95.83%) versus the control group (81.25%) (p < 0.05). The time to onset of pain relief was shortened, the duration of pain relief was prolonged, and VAS scores for pain level were lower in the experimental than the control group (p < 0.05). Among patients in the experimental group, the number of oral ulcers and ulcer area decreased, and faster onset of pain relief and time until normal eating improved in comparison to the control group (p < 0.05). Reduced levels of IL-2, IL-6, IL-8, and TNF-α were observed in the experimental vs the control group (p < 0.05). Elevated levels of CD3+, CD4+, and NKT and reduced levels of CD8+ were found in the experimental group compared to the control group (p < 0.05). The ulcer recurrence rate of patients in the experimental group (8.33%) was notably lower in comparison to the control group (29.17%). Conclusion: Chlorhexidine gargle plus rb-bFGF gel can improve the clinical outcome of patients with recurrent oral ulcers. It can reduce the levels of inflammatory factors, improve immune function, and reduce the recurrence rate. [ABSTRACT FROM AUTHOR]

Purpose: Menthol mouth swills can improve endurance performance in the heat, which is attributed to attenuations in nonthermally derived thermal sensation (TS) and perception of effort. However, research in elite team-sport athletes is absent. Therefore, this study investigated the performance and TS responses to a 0.1% menthol mouth rinse (MR) or placebo (PLA) among elite male rugby union players. Method: Twenty-seven (15 Forwards and 12 Backs) elite male Super Rugby players completed two 3-minute 15-a-side rugby-specific conditioning blocks, with MR or PLA provided at the start of training (baseline), at the start of each 3-minute block (swill 1 [S1] and swill 2 [S2]), and at the end of training (swill 3 [S3]). TS was assessed using the American Society of Heating, Refrigerating and Air-Conditioning Engineers 9-point Analog Sensation Scale after each swill and at baseline (preconditioning block). Acceptability was measured after baseline swill and S3 using a 5-question Likert scale. Physical performance was measured throughout training using global positioning system metrics. Results: MR attenuated TS from baseline to S1 (P =.003, SD = 1.01) and S2 (P =.002, SD = 1.09) in Forwards only, compared with PLA. Acceptability was higher only for Forwards in MR versus PLA at baseline (P =.003, SD = 1.3) and S3 (P =.004, SD = 0.75). MR had no effect on physical performance metrics (P >.05). Conclusion: MR attenuated the rise in TS with higher acceptability at S1 and S3 (in Forwards only) with no effect on selected physical performance metrics. Longer-duration exercise (eg, a match) in hot–humid conditions eliciting markedly increased body temperatures could theoretically allow favorable changes in TS to enhance performance—these postulations warrant experimental investigation. [ABSTRACT FROM AUTHOR]

Rationale: Tramadol (T) is a strong painkiller drug that belongs to the opioid analgesic group. Several accidental intoxication cases after oral administration of T have been reported in the past decade. Tramadol, its derivatives, and metabolites present information‐limited mass spectra with one prominent peak representing the amine‐containing residue; therefore, their structural determination based on both electron impact mass spectrometry (EI‐MS) and ESI‐MS/MS spectra could be misleading. Methods: A novel analytical method for the structural elucidation of tramadol, its four homologs, and its two main phase I metabolites (N‐desmethyltramadol and O‐desmethyltramadol) was developed using chemical modification and liquid chromatography–high‐resolution tandem mass spectrometry (LC‐HR‐MS/MS) with Orbitrap technology. Results: After chemical derivatization, each of the investigated T series exhibited informative mass spectra that enabled better exposition of their structures. The developed method was successfully implemented to explicitly identify the structures of tramadol and its N‐desmethyltramadol metabolite in urine samples at low ng/mL levels. Conclusions: An efficient derivatization‐aided strategy was developed for rapidly elucidating the structure of tramadol‐like compounds. The method is intended to assist forensic chemists in better diagnosing T and its analogs and metabolites in clinical or forensic toxicology laboratories. [ABSTRACT FROM AUTHOR]

The prospective of percutaneous drug delivery (PDD) mechanisms to address the limitations of oral and injectable treatment for rheumatoid arthritis (RA) is increasing. These limitations encompass inadequate compliance among patients and acute gastrointestinal side effects. However, the skin's intrinsic layer can frequently hinder the percutaneous dispersion of RA medications, thus mitigating the efficiency of drug delivery. To circumvent this constraint, we developed a strontium ranelate (SrR)-loaded alginate (ALG) phototherapeutic hydrogel to assess its effectiveness in combating RA. Our studies revealed that this SrR-loaded ALG hydrogel incorporating photoelectrically responsive molybdenum disulfide nanoflowers (MoS2 NFs) and photothermally responsive polypyrrole nanoparticles (Ppy NPs) to form ALG@SrR-MoS2 NFs-Ppy NPs demonstrated substantial mechanical strength, potentially enabling delivery of hydrophilic therapeutic agents into the skin and significantly impeding the progression of RA. Comprehensive biochemical, histological, behavioral, and radiographic analyses in an animal model of zymosan-induced RA demonstrated that the application of these phototherapeutic ALG@SrR-MoS2 NFs-Ppy NPs effectively reduced inflammation, increased the presence of heat shock proteins, regulatory cluster of differentiation M2 macrophages, and alleviated joint degeneration associated with RA. As demonstrated by our findings, treating RA and possibly other autoimmune disorders with this phototherapeutic hydrogel system offers a distinctive, highly compliant, and therapeutically efficient method. [ABSTRACT FROM AUTHOR]

Background: Despite the application of various tools for the control of vectors of Plasmodium falciparum, malaria remains the major killer disease in sub-Saharan Africa accounting for up to 90% of deaths due to the disease. Due to limitations of the useage of chemical insecticides such as resistance, negative impact on the environment and to nontarget organisms, the World Health Organization (WHO) requires that affected countries find alternative vector control tools. This study evaluated the effectiveness of (+)-usnic acid (UA) as an insecticide through oral administration to male and female Anopheles gambiae as an alternative or additional active ingredient to be used in toxic sugar bait. Methods: (+)-usnic acid was diluted using acetone at 5, 10, and 15 mg/ml concentrations in three replicates. A 5 ml mixture of 2% food dye and 10% sugar using chlorine-free water mixed with the dilutions of the (+)-usnic acid and negative control was made containing 2% food dye and 10% sugar solution. The preparations were soaked on a ball of cotton wool and placed over the net of a cup. 5 male and 5 non-blood-fed female newly hatched starved An. gambiae Kisumu strain were introduced together into a cup and monitored for knockdown and mortalities after 4, 24 48, and 72 h. The data were analysed using a multiple linear regression model using the lm function, a base R function and a posthoc test were conducted on the significant main effects and interaction terms using the emmeans function from the emmeans R package. All analyses were performed in RStudio using base R (version 4.3.3). Results: There was high mortality of both male and female An. gambiae after ingestion of the toxic sugar bait. 15 mg/ml usnic acid caused the highest mortality (50%) within the first 4 h compared to 5 and 10 mg/ml (+)-UA. There was a decline in the mortality rate with increased exposure time from 24 to 72 h, however, there was a significant difference in mortality at 5, 10 and 15 mg/ml. Acute toxicity was associated with ingestion of 15 mg/ml after 24 h. 72 h post-mortality was lower in all concentrations than in the control. High mortality was observed among females over the first 4 h (60%) compared to males (40%) due to higher feeding rate of the toxic agent. The proportion of dead males and females was equal after 24 h while after 48 h, the proportion of dead males was high.There was a significantly lower mortality rate after 72 h for both males and females (0 to 13.3%). Compared to all the treatments, high mortality of males was observed. Conclusions: The results of this study indicate that (+)-UA when administered as oral sugar bait to An. gambiae has insecticidal properties and is a suitable ingredient to be used as a toxic agent in the novel attractive toxic sugar bait for the control of malaria vectors. (+)-UA may be an alternative active ingredient as toxic bait in the effort to reduce and eliminate the transmission of Plasmodium falciparum in Africa. [ABSTRACT FROM AUTHOR]

Azilsartan is an angiotensin II receptor blocker used for treating adult hypertension. It significantly improves cardiovascular outcomes in patients with high‐risk hypertension, heart failure, and diabetic nephropathy. A single‐center, randomized, open‐label, single‐dose, dual‐cycle, dual‐crossover clinical trial was conducted to evaluate the bioequivalence of azilsartan under fasting and postprandial conditions in 60 Chinese healthy volunteers. Thirty healthy subjects were enrolled in each test group, with random cross‐administration for fasting and postprandial tests. The concentration of azilsartan in human plasma was evaluated using liquid chromatography‐tandem mass spectrometry after a single oral administration of test and reference preparations, each at a dose of 20 mg (1 tablet). Pharmacokinetic parameters were determined using WinNonlin8.2 software, and bioequivalence was evaluated using SAS 9.4 software. The geometric mean ratios and 90% confidence intervals for maximum concentration, area under the plasma concentration‐time curve from time 0 to the time of last measurable concentration, and area under the plasma concentration‐time curve from time 0 to infinity of the test and reference preparations in the fasting and postprandial test groups were in the range of 80%‐125%. The incidence of adverse events in the fasting and postprandial test groups was 30% (9/30) and 33.3% (10/30), respectively. No serious adverse events or unexpected adverse drug reactions were observed. In conclusion, the test and reference preparations of azilsartan tablets demonstrate bioequivalence and good safety in healthy Chinese subjects under fasting and postprandial conditions. [ABSTRACT FROM AUTHOR]

Key points Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol‐induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol‐induced AP. Intact guinea‐pig pancreatic ducts were pre‐treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX‐809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi‐treated guinea‐pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose‐dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol‐induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol‐induced pancreatitis. This is the first in vivo pre‐clinical evidence of Orkambi efficacy in the treatment of alcohol‐induced AP. Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3– secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol‐induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol‐induced pancreatitis by enhancing pancreatic functions or preventing recurrence. [ABSTRACT FROM AUTHOR]

• ALCAR attenuated autism-like behaviors. • ALCAR alleviated hippocampal oxidative stress in autistic rats. • ALCAR prevented reduction of parvalbumin-positive interneurons. • ALCAR reduced dysregulation of mitochondrial biogenesis. This study aimed to evaluate the potential benefits of acetyl-L-carnitine (ALCAR) in the context of valproate-induced autism. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p.) on embryonic day 12.5, followed by ALCAR treatment (300 mg/kg on postnatal days 21–49, p.o.), assessment of oxidative stress, mitochondrial membrane potential (MMP), mitochondrial biogenesis, parvalbumin interneurons, and hippocampal volume was conducted. These assessments were carried out subsequent to the evaluation of autism-like behaviors. Hippocampal analysis of oxidative factors (reactive oxygen species and malondialdehyde) and antioxidants (superoxide dismutase, catalase, and glutathione) revealed a burden of oxidative stress in VPA rats. Additionally, mitochondrial biogenesis and MMP were elevated, while the number of parvalbumin interneurons decreased. These changes were accompanied by autism-like behaviors observed in the three-chamber maze, marble burring test, and Y-maze, as well as a learning deficit in the Barnes maze. In contrast, administrating ALCAR attenuated behavioral deficits, reduced oxidative stress, improved parvalbumin-positive neuronal population, and properly modified MMP and mitochondrial biogenesis. Collectively, our results indicate that oral administration of ALCAR ameliorates autism-like behaviors, partly through its targeting oxidative stress and mitochondrial biogenesis. This suggests that ALCAR may have potential benefits ASD managing. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS. Methods: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups. Results: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005). Conclusion: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS. [ABSTRACT FROM AUTHOR]

Background In 2019, the World Health Organization called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three 9-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. Methods We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. Results Of 510 participants, 41% were women, the median age was 37 years (25th–75th percentile: 28–49), 18% had a body mass index <18.5 kg/m2, and 51% had cavitary disease. A total of 399 (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% CI: 89–95%), 89% (95% CI: 80–94%), and 100% (95% CI: 86–100%) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz, respectively. Clinically relevant adverse events of special interest were uncommon. Conclusions All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus bloodstream infection (bacteremia) is traditionally treated with at least 2 weeks of intravenous (IV) antibiotics in adults, 3–7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteremia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. Protocol The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 ±2 (uncomplicated SAB) and day 14 ±2 (complicated SAB) to determine their eligibility for randomization to EOS (intervention) or continued IV treatment (current standard of care). Discussion Recruitment is occurring in the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomized to the EOS domain, a total of 264 participants across 77 centers, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Melasma is a chronic condition characterized by dark patches on the facial skin. It has a known female gender dominancy, and women usually think of melasma as being a serious cosmetic problem. Treatment of melasma can be seriously challenging, thus, dermatologists may employ different approaches for melasma. This study aimed to investigate how dermatologists diagnose and treat patients with melasma and to present the general characteristics of patients with melasma.A survey was conducted using Google Forms targeting dermatologists in Turkiye. A total of 199 dermatologists (142 females/57 males) participated in the study.Most of the participants (52.3%) were residents. Majority gender of the patients was female and most common age range of patients with melasma was 30–40 years. Mixed melasma was the most common type (57.4%). Malar region was the most frequent location (58.6%). Wood's lamp examination was used by 25.6% of the participants. Topical treatment was the first‐line choice for melasma therapy (95%), with Kligman's formula being the most used topical agent (69.8%). Oral therapy was not used by 70.8% of the participants. Tranexamic acid was the first choice for oral treatment (23.4%). Only 24.9% of the dermatologists used laser/light therapy, and Q‐switched Nd‐YAG laser was the most preferred device (58%). The most common recurrence rate was 41%–60% (45.9%).The findings of the current study investigating the melasma management in Turkiye revealed a female predominance and peak prevalence in the 30–40 years age group. Kligman's formula is the preferred topical treatment, whereas oral tranexamic acid remains underutilized. Recurrence rates are high, highlighting the need for preventative strategies. This study emphasizes the importance of personalized approaches and ongoing research for effective melasma management. [ABSTRACT FROM AUTHOR]

Introduction: Treatment with topotecan is standard-of-care therapy for relapsed small-cell lung cancer (SCLC). Both oral and intravenous administrations of topotecan have been extensively researched and are found to be equally effective with less adverse events in the oral group. Case Presentation: We report a case of a patient with SCLC, who had previously received oral topotecan, with radiological stable disease with no changes in tumor or metastasis diameter size after two administrations. Subsequently, this patient received intravenous topotecan instead of oral due to supply difficulties. After one administration of intravenous topotecan, we saw significant disease regression. Conclusion: This is to our knowledge the first reported case of better response of intravenous topotecan than oral topotecan. Multiple extrinsic (e.g., food, medication) factors were investigated but could not deliver an explanation. [ABSTRACT FROM AUTHOR]

Background: Warfarin and Direct Oral Anticoagulant (DOAC) users may have more frequent antibiotic prescriptions than non-users. The aim of this study was to estimate rates of common and resistant infections, and antibiotic prescribing amongst warfarin and DOAC users versus non-users. Methods: This matched retrospective cohort study used data from patients registered with General practices in England contributing to the Clinical Practice Research Datalink GOLD. We included 61,750 adults who initiated warfarin or a DOAC between 1st January 2011 and 31st December 2019, matched 1:1 to non-users. We estimated Incident Rate Ratios (IRR) and 95% Confidence Intervals for three common infections and all-cause antibiotic prescribing. We estimated hazard ratios (HRs) and 95% CIs for the risk of methicillin resistance Staphylococcus aureus (MRSA), other antibiotic-resistant organisms, or Clostridium difficile. We assessed the extent to which any of the effect of warfarin and DOAC use on antibiotic resistant infections or Clostridium difficile was mediated by antibiotic prescribing patterns. Results: 37,143 warfarin users and 24,607 DOAC users were matched 1:1 to non-users. Warfarin and DOAC users had greater relative consultation rates for respiratory, urinary, and skin infections. All-cause antibiotic prescribing was greater in warfarin and DOAC users (warfarin; adjusted IRR 1.47, 95% CI 1.45–1.50, DOAC; adjusted IRR 1.66, 95% CI 1.63–1.69). Largest effect sizes were observed for flucloxacillin (adjusted IRR 2.11, 95% CI 2.01–2.20), and erythromycin (adjusted IRR 2.32, 95% CI 2.00–2.70). Warfarin users had significantly higher risk of MRSA (adjusted HR 1.68, 95% CI 1.38–2.05) and hospital admission with antibiotic resistant infections (adjusted HR 1.91, 95% CI 1.11–3.30). DOAC users had significantly higher risk of MRSA (adjusted HR 1.57, 95% CI 1.20–2.06), hospital admission with antibiotic resistant infections (adjusted HR 2.13, 95% CI 1.61–2.82), and Clostridium difficile (adjusted HR 1.45, 95% CI 1.10–1.92). We found little evidence to suggest that the increased risks of studied outcomes were mediated by rates of antibiotic prescription. Conclusion: Warfarin and DOAC use was associated with greater rates of infection consultations, all-cause antibiotic prescribing, antibiotic resistant infections, and Clostridium difficile, but there was little evidence that antibiotic prescribing rates mediated risk of resistant infections or Clostridium difficile. [ABSTRACT FROM AUTHOR]

Rationale: Eucommia cortex is the core herb in traditional Chinese medicine preparations for the treatment of osteoporosis. Pinoresinol diglucoside (PDG), the quality control marker and the key pharmacodynamic component in Eucommia cortex, has attracted global attention because of its definite effects on osteoporosis. However, the in vivo metabolic characteristics of PDG and its anti‐osteoporotic mechanism are still unclear, restricting its development and application. Methods: Ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry was used to analyze the metabolic characteristics of PDG in rats, and its anti‐osteoporosis targets and mechanism were predicted using network pharmacology. Results: A total of 51 metabolites were identified or tentatively characterized in rats after oral administration of PDG (10 mg/kg/day), including 9 in plasma, 28 in urine, 13 in feces, 10 in liver, 4 in heart, 3 in spleen, 11 in kidneys, and 5 in lungs. Furan‐ring opening, dimethoxylation, glucuronidation, and sulfation were the main metabolic characteristics of PDG in vivo. The potential mechanism of PDG against osteoporosis was predicted using network pharmacology. PDG and its metabolites could regulate BCL2, MARK3, ALB, and IL6, involving PI3K‐Akt signaling pathway, estrogen signaling pathway, and so on. Conclusions: This study was the first to demonstrate the metabolic characteristics of PDG in vivo and its potential anti‐osteoporosis mechanism, providing the data for further pharmacological validation of PDG in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Cationic calcium ions can crosslink anionic alginate and pectin molecules. It was hypothesized that calcium crosslinking would improve the stability and functionality of biopolymer nanoparticles consisting of zein cores coated by alginate‐pectin shells. The effects of calcium ion addition on the structural, physicochemical, and gastrointestinal properties of quercetin‐loaded zein/alginate‐pectin nanoparticles were therefore investigated.The nanoparticles remained stable to aggregation at calcium ion concentrations of 9 mmol/L or less but aggregated and sedimented at higher concentrations. Calcium ion reinforcement increased the particle dispersion stability even at NaCl concentrations up to 1.4 molL‐1. The presence of the calcium ions also reduced quercetin release during the early stages of simulated gastrointestinal digestion but increased its release during the later stages. The relatively high release (56.1%) of quercetin from the calcium‐reinforced nanoparticles after digestion resulted in higher intracellular antioxidant activities. The pharmacokinetics of the encapsulated quercetin was measured after its oral administration to rats. The maximal concentration (Cmax) of quercetin in rat plasma for calcium‐reinforced nanoparticles was 6.1% higher than non‐reinforced nanoparticles; the half‐life (t1/2) increased by 17.5%, and the mean retention time (MRT) was 10.0% higher (P < 0.05).These results suggest that calcium ion addition improved the performance and bioavailability of nutraceutical‐loaded biopolymer nanoparticles. This might find application in the food and beverage industry. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Physiologically Based Pharmacokinetic (PBPK) models can provide forecasts of the drug residues within the organism. Ractopamine (RAC) is a typical β-agonist. In this study, we developed a PBPK model for RAC in goats. The goal was to predict the distribution of the drug after multiple oral administrations. The preliminary PBPK model for RAC in goats performed well in predicting the drug's distribution in most tissues. In our sensitivity analysis, we found that the parameter of Qclu (Blood Flow Volume through Lungs) had the greatest impact on the RAC concentrations in plasma, liver, and kidney and was the most sensitive parameter. Furthermore, our study aimed to assess the withdrawal time (WT) of RAC in different tissues after RAC long-term exposure in goats. We found that the WT of RAC in the kidney was the longest, lasting for 13 days. Overall, the insights gained from this study have important implications for optimizing drug administration in goats and ensuring appropriate withdrawal times to prevent any potential risks. [ABSTRACT FROM AUTHOR]

Purpose: Rhubarb (Rheum palmatum L.) and astragalus (Radix astragali) find widespread used in clinical formulations for treating chronic kidney disease (CKD). Notably, the key active components, total rhubarb anthraquinone (TRA) and total astragalus saponin (TAS), exhibit superiority over rhubarb and astragalus in terms of their clear composition, stability, quality control, small dosage, and efficacy for disease treatment. Additionally, astragalus polysaccharides (APS) significantly contribute to the treatment of renal fibrosis by modulating the gut microbiota. However, due to differences in the biopharmaceutical properties of these components, achieving synergistic effects remains challenging. This study aims to develop combined pellets (CPs) and evaluate the potential effect on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Methods: The CPs pellets were obtained by combining TRA/TAS-loaded SNEDDS pellets and APS-loaded pellets, prepared using the fluidized bed coating process. The prepared pellets underwent evaluation for morphology, bulk density, hardness, and flowing property. Moreover, the in vitro release of the payloads was evaluated with the CHP Type I method. Furthermore, the unilateral ureteral obstruction (UUO) model was utilized to investigate the potential effects of CPs pellets on renal fibrosis and their contribution to gut microbiota modulation. Results: The ex-vivo study demonstrated that the developed CPs pellets not only improved the dissolution of TRA and TAS but also delivered TRA/TAS and APS spatiotemporally to the appropriate site along the gastrointestinal tract. In an animal model of renal fibrosis (UUO rats), oral administration of the CPs ameliorated kidney histological pathology, reduced collagen deposition, and decreased the levels of inflammatory cytokines. The CPs also restored the disturbed gut microbiota induced by UUO surgery and protected the intestinal barrier. Conclusion: The developed CPs pellets represent a promising strategy for efficiently delivering active components in traditional Chinese medicine formulas, offering an effective approach for treating CKD. [ABSTRACT FROM AUTHOR]

Background: Salidroside (SDS), a phenylpropanoid glycoside, is an antioxidant component isolated from the traditional Chinese medicine Rhodiola rosea and has multifunctional bioactivities, particularly possessing potent hepatoprotective function. Non-alcoholic steatohepatitis (NASH) is one of the most prevalent chronic liver diseases worldwide, but it still lacks efficient drugs. This study aimed to assess the preventive and therapeutic effects of SDS on NASH and its underlying mechanisms in a mouse model subjected to a methionine- and choline-deficient (MCD) diet. Methods: C57BL/6J mice were fed an MCD diet to induce NASH. During or after the formation of the MCD-induced NASH model, SDS (24 mg/kg/day) was supplied as a form of diet for 4 weeks. The histopathological changes were evaluated by H&E staining. Oil Red O staining and Sirius Red staining were used to quantitatively determine the lipid accumulation and collagen fibers in the liver. Serum lipid and liver enzyme levels were measured. The morphology of autophagic vesicles and autophagosomes was observed by transmission electron microscopy (TEM), and qRT-PCR and Western blotting were used to detect autophagy-related factor levels. Immunohistochemistry and TUNEL staining were used to evaluate the apoptosis of liver tissues. Flow cytometry was used to detect the composition of immune cells. ELISA was used to evaluate the expression of serum inflammatory factors. Transcript-proteome sequencing, molecular docking, qRT-PCR, and Western blotting were performed to explore the mechanism and target of SDS in NASH. Results: The oral administration of SDS demonstrated comprehensive efficacy in NASH. SDS showed both promising preventive and therapeutic effects on NASH in vivo. SDS could upregulate autophagy, downregulate apoptosis, rebalance immunity, and alleviate inflammation to exert anti-NASH properties. Finally, the results of transcript-proteome sequencing, molecular docking evaluation, and experimental validation showed that SDS might exert its multiple effects through targeting PPARα. Conclusion: Our findings revealed that SDS could regulate liver autophagy and apoptosis, regulating both innate immunity and adaptive immunity and alleviating inflammation in NASH prevention and therapy via the PPAR pathway, suggesting that SDS could be a potential anti-NASH drug in the future. [ABSTRACT FROM AUTHOR]

Introduction: Allergic rhinitis (AR) is a widespread upper airway disorder characterized by inflammation of the nasal passages. It is immunologically mediated via the hypersensitivity type I mechanism, which is primarily elicited by the immunoglobulin E (IgE)-linking allergen-induced imbalance of the Th2/Th1 immune response. Owing to the limited efficacy of current medications, probiotics have received attention for their potential in preventing and ameliorating AR. Methods: In this study, a Lacticaseibacillus paracasei strain, GOLDGUTLpc969 (Lpc969), isolated from the feces of healthy adults, was proven to be effective in preventing AR by LPA-induced RBL-2H3 in-vitro and OVA-induced AR mice invivo evaluation. Results: The strain significantly attenuated the release of histamine and degranulation in LPS-induced RBL-2H3 cells. In the OVA-induced AR mice, L. paracasei GOLDGUT-Lpc969 also exhibited a significant decrease in disease indicators such as the disease activity index (DAI score), serum IgE, and serum histamine. Treatment with L. paracasei GOLDGUT-Lpc969 led to significant suppression of the Th2-related cytokines IL-4, IL-5, IL-6, IL-13, and TNF-a in the serum of mice. Discussion: Furthermore, a comparison of the genomes of three previously reported AR-effective L. paracasei strains (including GOLDGUTLpc969) and one non-effective L. paracasei strain revealed that the gene K03671 may play a key role in alleviating AR symptoms. In conclusion, this study highlights the efficacy of L. paracasei GOLDGUT-Lpc969 in AR prevention by suppressing the Th2 immune response and proposes the potential involvement of the functional gene K03671 in ameliorating AR symptoms. Therefore, L. paracasei GOLDGUTLpc969 shows promise as a probiotic for preventing AR. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Cyclophosphamide (CP) is used as antineoplastic agent. However, anticancer therapy is largely impeded by its toxicity arising from oxidative stress. Strategies that can attenuate this off‐target effect of CP could be helpful. Commelina benghalensis L. is widely used in oriental traditional medicine for management of jaundice, fever, inflammation, leprosy and snake bites; its potential against chemotherapy‐induced hepatotoxicity is unknown. The present study evaluates the hepatoprotective effect of hydro‐ethanolic extract of C. benghalensis (HECB) in a rat model of CP‐induced hepatotoxicity.Chemical characterization of HECB was carried out followed by 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assay. Hepatic functional tests including phenobarbitone‐induced sleeping time were done and anti‐oxidant reserves were estimated after oral treatments at 50 and 100 mg/kg for eight weeks. Inflammatory markers and mitochondrial integrity (complex I activity, nuclear factor erythroid 2–related factor 2 [Nrf2] and mitochondrial transcriptional factor A [TFAM] levels) were analyzed in the tissue lysates.Flavonoids and phenolic compounds were found at higher concentrations of 50 and 100 μg/mL with a significant free radical scavenging activity as displayed by DPPH assay. Administration of CP has resulted in increased liver weight, elevated serum hepatic enzyme activity along with inflammatory markers, decreased hepatic anti‐oxidant reserves, and impaired mitochondrial activity. Correspondingly, daily oral administration of HECB ameliorated these parameters and restored anti‐oxidant reserves. Further, hepatic mitochondrial activity, Nrf2 and TFAM levels were also improved. The hepatoprotective effect of HECB was further confirmed by histopathological analysis and phenobarbitone‐induced sleeping time.Conclusively, the study provides preliminary evidence regarding the hepatoprotective activity of HECB and the contribution of its anti‐oxidant potential towards this pharmacological effect. [ABSTRACT FROM AUTHOR]

The rising incidence rate of depression presents a substantial threat to human well‐being. Semen Trigonellae (ST), the dried mature seeds of Trigonella foenum‐graecum L., has a long‐standing traditional reputation for alleviating anxiety and hopelessness. However, the anti‐depressant mechanism of ST remains poorly understood. This study aimed to assess ST's anti‐depressant, as well as explore its potential mechanism from a gut microbial aspect. The Kunming mice were challenged by lipopolysaccharide (LPS) to induce depression‐like behavior and then orally administrated with aqueous extract of ST. The behavioral test, and hippocampal and serum biochemical indicators were detected to assess anti‐depressant effect of ST. We utilized full‐length 16S rRNA gene sequencing to investigate how ST influences gut microbiota modulation. Administration of ST mitigated LPS‐induced depression‐like behaviors. ST reversed the decrease in hippocampal 5‐hydroxytryptamine (5‐HT) and brain‐derived neurotrophic factor (BDNF) levels while reducing serum levels of tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β), and interleukin 6 (IL‐6). Microbial analysis revealed that administration of ST markedly shifted the gut microbiota structure, dramatically and dose‐dependently increased the abundance of Ligilactobacillus murinus and Ligilactobacillus animalis. Experimentally, oral administration of live L. murinus and L. animalis to LPS‐challenged mice yielded similar effects to ST in ameliorating depression, elevating 5‐HT and BDNF, and reducing proinflammatory cytokines. These findings provide evidence that ST is a promising medical food for the management of depression, in which modulation of the gut microbiota, particularly enhancing the abundance of Ligilactobacillus plays an important role. [ABSTRACT FROM AUTHOR]

AbstractEmpagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently reported to prevent the depression in chronic animal model. The present study aimed to explore the antidepressant potential of empagliflozin using a neuroinflammation-mediated depression involving the olfactory bulbectomy (OBX) model in diabetic rats. A low dose of streptozotocin was injected to induce diabetes in all group of animals. Following the confirmation of hyperglycemia, OBX surgery was performed. Post-surgery, the drug treatments were administered orally for 14 consecutive days. The study evaluated the effects of daily oral administration of empagliflozin at doses of 5 and 10 mg/kg, alongside metformin (200 mg/kg) and clomipramine (50 mg/kg), on OBX-induced behavioral depression in rats. Separate sham and vehicle control groups were also maintained. Behavioral parameters in open field, forced swim test, elevated plus maze and splash test were recorded on 28th day. Results showed that empagliflozin, at the higher dose, significantly enhanced behavioral outcomes, evidenced by increased distance travelled, greater open arm entries, and reduced immobility, alongside a notable reduction in grooming time. Moreover, empagliflozin significantly restored the antioxidants level specifically Glutathione (GSH) and Catalase (CAT) in OBX insulted rat brain and decreased Lipid peroxidase (LPO). Notably, molecular docking study demonstrated a good binding affinity of empagliflozin for Brain-Derived Neurotrophic Factor (BDNF), suggesting that its antidepressant effects may be mediated through the modulation of the BDNF pathway. These findings support the potential therapeutic application of empagliflozin for depression, particularly in cases associated with neuroinflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model. [ABSTRACT FROM AUTHOR]

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis. [ABSTRACT FROM AUTHOR]

Background: Embryonal rhabdomyosarcoma (ERMS) is a highly aggressive form of soft-tissue sarcoma that predominantly affects children. Due to limited benefits and resistance to therapy, there is an unmet need to explore alternative therapeutic strategies. Case presentation: In this report, we present a rare case of pediatric ERMS located on the right side of the maxillary gingiva. A composite reference guide integrating clinical, radiographic, and histopathologic findings was used for a definitive diagnosis. Targeted next-generation sequencing of tumor biopsy was performed to identify genetic alterations. A 12-year-old female was admitted to the Pediatric Intensive Care Unit (PICU) and underwent a tracheotomy to relieve asphyxiation caused by a 5.5 cm diameter mass compressing the tongue root and pharyngeal cavity. Hematoxylin and eosin staining revealed a hybrid morphology characterized by clusters of round and spindle cells. Further immunohistochemistry assays indicated positive immunoreactivity for desmin, myogenin, and MyoD1. Various genetic alterations were identified, including mutations in GNAS, HRAS, LRP1B, amplification of MDM2 and IGF1R, and two novel IGF1R fusions. Negative PAX-FOXO1 fusion status supported the clinical diagnosis of ERMS. Initial treatment involved standard chemotherapy; however, the tumor persisted in its growth, reaching a maximum volume of 12 cm × 6 cm × 4 cm by the completion of treatment. Subsequent oral administration of anlotinib yielded a significant antitumor response, characterized by substantial tumor necrosis and size reduction. Following the ligation of the tumor pedicle and its removal, the patient developed a stabilized condition and was successfully discharged from PICU. Conclusions: Our study highlights the importance of accurate diagnosis established on multifaceted assessment for the effective treatment of ERMS. We present compelling evidence supporting the clinical use of anlotinib as a promising treatment strategy for pediatric ERMS patients, especially for those resistant to conventional chemotherapy. [ABSTRACT FROM AUTHOR]

Bleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually "blinded" with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) belongs to chronic inflammatory disease with a relapsing characterization. Conventional oral drugs of UC are restricted in clinical by premature degradation in the gastrointestinal tract, modest efficacy, and adverse effects. CX5461 can treat autoimmune disease, immunological rejection, and vascular inflammation. However, low solubility, intravenous administration, and non-inflammatory targeting limited its clinical application. Herein, this work aims to develop Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 (SFELNVs@CX5461) for efficient CX5461 oral delivery for UC therapy. We identified SFELNVs as nano-diameter (80 nm) with negative zeta potential (-32mV). Cellular uptake has shown that SFELNVs were targeted uptake by macrophages, thus increasing drug concentration. Additionally, oral SFELNVs@CX5461 exhibited good safety and stability, as well as inflammation-targeting ability in the gastrointestinal tract of dextran sodium sulfate (DSS)-induced colitis mice. In vivo, oral administration of SFELNVs and CX5461 could relieve mice colitis. More importantly, combined SFELNVs and CX5461 alleviated mice colitis by inhibiting pro-inflammatory factors (TNF-α, IL-1β, and IL-6) expression and promoting M2 macrophage polarization. Furthermore, SFELNVs promoted M2 polarization by miR4371c using miRNA sequencing. Our results suggest that SFELNVs@CX5461 represents a novel orally therapeutic drug that can ameliorate colitis, and a promising targeting strategy for safe UC therapy. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disorder for which effective treatments remain limited. Recent investigations revealed a potential link between altered glucose metabolism and the activation of fibroblasts, the key cells responsible for generating and depositing extracellular matrix proteins within the lung interstitium during IPF development. Method: In this study, we aimed to investigate the potential therapeutic impact of albendazole on fibroblast to myofibroblast transition in IPF. We assess albendazole's effectiveness in attenuating the activation of fibroblasts. We focused on elucidating the mechanism underlying albendazole's impact on TGF-β1-induced aerobic glycolysis in both lung tissues and fibroblasts obtained from patients with IPF and other lung fibrosis types. Furthermore, the antifibrotic effects of oral administration of albendazole were investigated in mouse models of pulmonary fibrosis induced by BLM or SiO2. Human precision-cut lung slices were employed to evaluate the impact of albendazole following TGF-β1 stimulation. Result: In this work, we demonstrated that albendazole, a first-line broad-spectrum anthelmintic drug, effectively attenuated fibroblast to myofibroblast transition through alleviating TGF-β1-induced aerobic glycolysis dependent on the LRRN3/PFKFB3 signaling pathway. Additionally, LRRN3 expression was downregulated in both lung tissues and fibroblasts from patients with IPF and other types of lung fibrosis. Importantly, the levels of LRRN3 correlated with the progression of the disease. Notably, oral administration of albendazole exerted potent antifibrotic effects in mouse models of pulmonary fibrosis induced by BLM or SiO2, and in human precision-cut lung slices after TGF-β1 stimulation, as evidenced by improvements in lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1 and Fibronectin expression in the lungs. Conclusion: Our study implies that albendazole can act as a potent agonist of LRRN3 during fibroblast to myofibroblast differentiation and its oral administration shows potential as a viable therapeutic approach for managing IPF. [ABSTRACT FROM AUTHOR]

Practical Application Oral administration of probiotics has demonstrated substantial potential in alleviating colitis. However, most of the ingested microorganisms struggle to survive the harsh conditions of the gastrointestinal tract, leading to decreased efficacy. In the present study, using double emulsification (W1/O/W2) and complex coacervation methods, we developed a gelatin/carboxymethyl cellulose (CMC)‐based probiotic microcapsule and analyzed the efficacy of encapsulated probiotics in preventing dextran sodium sulfate (DSS)‐induced colitis in mice. Our results reveal that nearly 90% of the encapsulated probiotics remained viable after 30‐day storage at 4°C and approximately 38.1% of viable bacteria (4.0 × 108 cfu/g) survived after 4‐h simulated gastrointestinal digestion. In a DSS‐induced colitis model, pretreatment with probiotics exerted significant protective effects, with the bacterial microcapsule‐treated group having superior outcomes to those of the bacterial suspension plus empty carrier group. Probiotic treatments, especially those administered in the encapsulated form, significantly increased fecal short‐chain fatty acid contents, and altered the intestinal microbial composition. The family Muribaculaceae, dominant bacteria in the mouse gut, may be the key microorganism involved in the BM regulation process. Our study presents an alternative approach to treating colitis using probiotics.The encapsuled probiotic showed remarkable storage stability at 4°C, maintained good vitality after simulated digestion, and gained superior outcomes in preventing colitis. Our results offer an alternative approach for the probiotic preparations aiming to prevent the intestinal inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Despite their dangerous side effects, opioid drugs remain a standard of care for moderate to severe pain with few alternatives. Strategies to maintain the analgesic effects of opioids while minimizing the associated risks are needed. Pre-clinical studies have shown using a dopamine 3 receptor (D3R) agonist as an adjuvant to morphine provides superior analgesia against painful stimuli compared to morphine alone. Our objective was to test if adjunct treatment with a D3R agonist can lead to a reduction in opioid use while maintaining effective analgesia. Patients and methods: This study was set up as a double-blinded, placebocontrolled randomized trial. Enrollment included acute renal colic patients presenting to the emergency department, from which patients were randomized to either the "control" or "study arm". The control group received standard treatment of care (morphine, 0.1 mg/kg; i.v.) and an oral placebo pill. The experimental group received half-dosed morphine and oral pramipexole pill (0.25 mg). Pain measurements including a numerical pain scale and visual analog scale were collected from enrollees at baseline and every subsequent 15 min. Results: A total of 19 patients completed the study, 10 in the experimental arm and 9 in the control arm. During the study period, effective analgesia (50% decrease from baseline) was achieved in 80% of patients in the experimental arm vs. 33.3% in the control arm. Conclusion: Our pilot clinical trial demonstrated that D3R recruitment can serve as an effective adjuvant to low-dose morphine for control of renal colic pain and potentially other acute pain conditions [ABSTRACT FROM AUTHOR]

Background: Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. It exhibits diverse biological activities, including immunomodulatory and anti-inflammatory properties; however, some of its activities have only been demonstrated in vitro. Objective: To examine the effects of orally administered AR extract on immune cells and the intestine under physiological conditions, which bridges the gap between previously observed in vitro outcomes and in vivo results. Methods: AR extract was prepared by hot water extraction. Three separate animal experiments were conducted to isolate macrophages, splenocytes, and the small intestine epithelium. For the macrophage preparation experiment, an intraperitoneal injection of sterile thioglycolate was administered. The mice received oral AR extract at doses of 0.1, 0.5, or 2.5 g/kg for ten days. At the end of each experiment, cells or tissues were isolated. A portion of macrophages and splenocytes were analyzed for the phenotypic changes. The remaining cells were cultured and stimulated with lipopolysaccharide (LPS) or mitogen ex vivo to assess activation status, proliferation, and cytokine production. Samples of the intestine were subjected to real-time RT-PCR. Results: Peritoneal macrophages from AR-treated mice exhibited increased expression of scavenger receptors, including SRA and CD36. Stimulation of these macrophages ex vivo with LPS selectively modulated the inflammatory response, including reduced expression of the costimulatory molecules CD40 and CD86, which are important for T cell responses, without affecting TNF-α and IL-6 production. Splenocytes from AR-treated mice exhibited a dose-dependent increase in CD4 and CD8 T cells; however, stimulation with mitogen decreased T cell proliferation and reduced IFN-γ production, which is essential for macrophage activation. An analysis of the small intestinal epithelium revealed an attenuated antimicrobial response, including reduced IgA content in the lumen and decreased expression of mucin-2 and polymeric Ig receptor genes. Conclusion: The response of immune cells following oral treatment with AR extract did not replicate the previously documented in vitro findings. Immune cells and intestinal epithelium from mice administered oral AR extract exhibited a selective anti-inflammatory phenotype. The overall findings indicate that the systemic effects after oral administration of AR extract include reduced sensitivity to inflammatory insults. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the influence of the CYP1A2 c.-163 A > C (rs762551) polymorphism on the effect of oral caffeine intake on fat oxidation during exercise. Methods: Using a pilot randomized, double-blind, crossover, placebo-controlled trial, 32 young and healthy individuals (women = 14, men = 18) performed an incremental test on a cycle ergometer with 3-min stages at workloads from 30 to 70% of maximal oxygen uptake (VO2max). Participants performed this test after the ingestion of (a) placebo; (b) 3 mg/kg of caffeine; (c) 6 mg/kg of caffeine. Fat oxidation rate during exercise was measured by indirect calorimetry. The influence of the CYP1A2 c.-163 A > C polymorphism in the effect of caffeine on fat oxidation rates during exercise was established with a three-way ANOVA (substance × genotype × intensity). Results: Eight participants were genotyped as AA, 18 participants were CA heterozygotes, and 6 participants were CC. There was a main effect of substance (F = 3.348, p = 0.050) on fat oxidation rates during exercise with no genotype effect (F = 0.158, p = 0.959). The post hoc analysis revealed that, in comparison to the placebo, 3 and 6 mg/kg of caffeine increased fat oxidation at 40–50% VO2max in AA (all p < 0.050) and 50–60% VO2max in CA and CC participants (all p < 0.050). Conclusion: Oral intake of 3 and 6 mg/kg of caffeine increased fat oxidation rate during aerobic exercise in individuals with AA, CA and CC genotypes. This suggests that the effect of caffeine to enhance fat oxidation during exercise is not influenced by the CYP1A2 c.-163 A > C polymorphism. Trial registration: The study was registered on clinicaltrials.gov with ID: NCT05975489. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is a systemic metabolic bone disease resulting in reduced bone strength and increased susceptibility to fractures, making it a significant public health and economic problem worldwide. The clinical use of anti‐osteoporosis agents is limited because of their serious side effects or the high cost of long‐term use. The Xianlinggubao (XLGB) formula is an effective traditional Chinese herbal medicine commonly used in orthopedics to treat osteoporosis; however, its mechanism of action remains unclear. In this study, we screened 40 small RNAs derived from XLGB capsules and found that XLGB28‐sRNA targeting TNFSF11 exerted a significant anti‐osteoporosis effect in vitro and in vivo by simultaneously promoting osteogenesis and inhibiting osteoclastogenesis. Oral administration of bencaosome [16:0 Lyso PA+XLGB28‐sRNA] effectively improved bone mineral density and reduced the damage to the bone microstructure in mice. These results suggest that XLGB28‐sRNA may be a novel oligonucleotide drug that promotes osteogenesis and inhibits osteoclastogenesis in mice. [ABSTRACT FROM AUTHOR]

Background: Patients with follicular lymphoma (FL) often relapse or become refractory to treatment (R/R). While the R/R FL treatment landscape evolves, little is known about the priorities of patients and physicians. This discrete‐choice experiment (DCE) study assessed patients' and physicians' treatment preferences, and the trade‐offs they would be willing to make between efficacy, tolerability, and administration. Methods: An online survey was conducted in US‐based patients (≥18 years) with R/R FL and FL‐treating physicians. The DCE was informed by a targeted literature review, clinical data, expert oncologist input, and pilot interviews. Participants completed eight experimental choice tasks where they chose between two hypothetical treatment profiles defined by six attributes: progression‐free survival (PFS), administration/monitoring, risks of laboratory abnormalities requiring intervention, severe infections, diarrhea, and cytokine release syndrome (CRS). Relative attribute importance (RAI) and willingness to trade‐off between PFS and other attributes were estimated. Results: Two‐hundred patients (mean age 63.5 years; median three prior lines of therapy) and 151 FL‐treating physicians participated. Increasing PFS was most important for both groups, although it was relatively less important to patients than physicians (RAI 35.2% vs. 45.7%). Administration/monitoring was three times more important to patients than physicians (RAI 28.8% vs. 9.5%); patients preferred oral treatment and would be willing to tolerate a significant reduction in PFS for oral administration over weekly intravenous infusions. Avoiding CRS was less important to patients than to physicians (RAI 7.7% vs. 15.8%). Both groups would accept shorter PFS for reduced risks of side effects (especially of laboratory abnormalities for patients and of CRS for physicians). Conclusion: Although PFS was the most important attribute to patients and physicians, both would tolerate lower PFS for reduced side effects. Patients would also accept a substantial reduction in PFS for oral administration. Differences between the preferences/priorities of patients and physicians highlight the importance of shared decision‐making. [ABSTRACT FROM AUTHOR]

The article in Clinical & Experimental Allergy explores how exposure to house dust mite (HDM) can promote the development of allergy to egg white in mice. The study found that inhalation of egg white and HDM led to systemic Th2 responses in mice, indicating a potential link between respiratory exposure to food allergens and systemic sensitization. The research suggests that prior sensitization to egg proteins through the respiratory tract, facilitated by HDM components, could lead to food allergies when egg is later ingested. The study highlights the adjuvant activity of HDM in enhancing the development of a Th2-driven immune response to egg white through the airways, with protease activity playing a modest role in this context. [Extracted from the article]

Herein, the pharmacokinetic profiles, binding interactions, and molecular properties of fluoroquinolone derivatives as prospective antiviral drugs are examined using a combination of docking, ADME, and DFT simulations. The effectiveness of the ligands is compared with the clinically tested and FDA-authorized medicine remdesivir. The findings demonstrated encouraging binding energies, indicating possible inhibitory effectiveness against SARS-CoV-2 Mpro. The fluoroquinolone derivatives also exhibit promising ADME characteristics, although compounds 5, 6, 9, 12–20 possess poor values, suggesting that oral administration may be possible. The potential of the selected compounds as SARS-CoV-2 Mpro inhibitors is thoroughly understood because of the integrated analysis of DFT, with compound 11 demonstrating the highest energy gap of 0.2604 eV of, docking with viral targets with docking scores of −7.9 to −5.9 kcal/mol, with compound 18 demonstrating the highest docking score, which is at the 13th position in energy difference in the DFT data. Their favorable electrical properties, robust binding interactions with viral targets, and attractive pharmacokinetic profiles boost their potential as prospective study subjects. These substances have the potential to be transformed into cutting-edge antiviral therapies that specifically target SARS-CoV-2 Mpro and related coronaviruses. [ABSTRACT FROM AUTHOR]

Objectives Performance evaluation of routine laboratory methods to determine the susceptibility of Enterobacterales urinary isolates to fosfomycin (oral administration) and mecillinam. Methods We collected 347 Enterobacterales isolates from monomicrobial midstream urine samples from women with significant bacteriuria and leukocyturia. Mostly non- Escherichia coli isolates (i.e. Klebsiella spp. Citrobacter koseri , Enterobacter cloacae complex and Proteus mirabilis) were included (n  = 298). Performance of VITEK®2, ETEST®, and disc diffusion to determine fosfomycin and mecillinam susceptibility was evaluated following International Organization for Standardization (ISO) 20776-2:2021 (or 20776-2:2007 for disc diffusion) in comparison with the agar dilution reference method. Results For fosfomycin testing, VITEK®2 and ETEST® were close to reaching ISO requirements (essential agreement  ≥ 90%; bias  ±30%) for C. koseri , E. coli and P. mirabilis. Categorical agreement (CA) and major error rates were acceptable for disc diffusion. Fosfomycin displayed lower activity against E. cloacae complex and Klebsiella spp. with MIC50 (minimum inhibitory concentration required to inhibit the growth of 50% of tested isolates) equal to the E. coli EUCAST breakpoint (8 mg/L). For these species, the three alternative techniques overestimated MICs and resistance, and did not meet performance criteria. For mecillinam testing of Enterobacterales isolates, apart from P. mirabilis , ETEST® nearly fulfilled ISO requirements, and CA rates were acceptable for disc diffusion. ISO criteria were reached for C. koseri and E. coli testing with VITEK®2, apart from too high rates of very major errors. For P. mirabilis, performances were unacceptable, whatever the routine method used. Conclusions Commercially available tests may serve as alternatives to agar dilution to assess fosfomycin (oral) and mecillinam susceptibility of Enterobacterales urinary isolates, with important interspecies variabilities. Additional studies comprising more fosfomycin- and mecillinam-resistant isolates are needed to strengthen our conclusions. [ABSTRACT FROM AUTHOR]

Corticosteroids play a crucial role as anti-inflammatory and immunomodulatory agents in dermatology and other medical specialties; however, their therapeutic benefits are accompanied by significant risks, especially in older adults. This review examines the broad spectrum of adverse effects (AEs) associated with oral corticosteroid therapy and offers strategies to prevent, monitor, and manage these issues effectively in older adults. AEs associated with systemic corticosteroids include immune suppression, gastrointestinal problems, hyperglycemia, insulin resistance, weight gain, cardiovascular complications, ocular issues, osteoporosis, osteonecrosis, muscle weakness, collagen impairment, psychiatric symptoms, and adrenal suppression. To minimize these AEs, tailored dosing and duration, frequent monitoring, and additional preventative measures can be employed to optimize corticosteroid treatment. By customizing management plans to the specific needs and risk factors associated with each patient, clinicians can promote the safe and effective use of oral corticosteroids, ultimately improving outcomes and quality of life in patients with inflammatory dermatologic disorders. [ABSTRACT FROM AUTHOR]

Objectives: modulation of gut microbiota by probiotics has been proposed as a target for intervention to reduce bone mineral density (BMD) loss in the postmenopausal period. This study aims to evaluate the effect of Lacticaseibacillus (L.) paracasei LPC100 and Lactiplantibacillus (L.) plantarum LP140 on BMD in postmenopausal women in a multicenter, randomized, double-blind, placebo-controlled trial. Methods: the primary outcome was the change in T-score of the lumbar spine measured by dual-energy X-ray absorptiometry assessed after twelve-month probiotic supplementation. Secondary outcomes included changes in serological markers of inflammation and calcium–phosphate metabolism, body mass index, gastrointestinal symptoms, and satisfaction with the intervention. Results: a decrease in T-score indicating the progressive bone demineralization reached a statistically significant difference in the placebo group (from mean values of 0.06 ± 1.04 to −0.28 ± 1.12, p = 0.041) but not in the probiotic group (0.19 ± 0.99 and −0.08 ± 1.05, respectively, p = 0.125) with a p-value = 0.089 between the groups. No significant differences were found in secondary outcomes with the exception of vitamin D concentration and a significant reduction in some gastrointestinal symptoms in the probiotic group. A significant decrease in vitamin D level was observed only in the placebo group (p = 0.014). Probiotics were safe and well tolerated. Conclusions: this study suggests that the oral administration of L. paracasei LPC100 and L. plantarum LP140 may be a viable strategy to prevent BMD loss and vitamin D deficiency in postmenopausal women, but further research is necessary to confirm clinical benefits and to know the mechanism of action [ClinicalTrial.gov NCT06375668]. [ABSTRACT FROM AUTHOR]

Background/Objective: It is not uncommon for elderly patients to experience difficulties with feeding and swallowing. In the simple suspension method, tablets are dissolved and suspended in warm water without prior crushing or decapsulation, and then administered via a tube. Despite the prevalence of this method, the pharmacokinetics of suspended tablet dosage forms remain poorly understood. Methods: Verapamil was employed in dissolution tests following both the simple suspension and crushing methods. A pharmacokinetics study was conducted on healthy adult males. Results: The resultant dissolution profiles from the two methods exhibited notable dissimilarities. Drug release from the crushed product commenced earlier than that from the simple suspension and intact tablet. Furthermore, the area under the curve for verapamil during the initial 24 h period was 1.7 and 1.3 times greater in the crushed and simple suspension groups, respectively, than in the tablet group. Conclusions: The crushing and simple suspension methods are safe techniques for administering medications to patients with dysphagia, thereby preventing aspiration. Nevertheless, the processing of medications may result in an increased frequency of adverse effects. It is recommended that the processing of medicines prior to administration be avoided. [ABSTRACT FROM AUTHOR]

Background: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator, which was demonstrated to reduce serum triglyceride levels with few drug-related adverse events in several clinical studies, as well as phase II and III clinical trials. One of the limitations of this medicine was the requirement of twice-daily oral administration, resulting in reduced medication adherence, particularly in elderly patients, who are rather good targets for this medicine. Recently, a once-daily extended-release (XR) tablet has been introduced. Given an improvement in medication adherence, the therapeutic efficacy of pemafibrate may be enhanced. Methods: Patients with hypertriglyceridemia, in whom conventional twice-daily immediate-release (IR) pemafibrate was converted to pemafibrate XR between 2023 and 2024, were eligible. Each type of tablet was prescribed for three months, respectively. A dose change was not attempted. The serum triglyceride levels were compared between 3 months pre-conversion and 3 months post-conversion using a Friedman test and a post hoc Wilcoxon signed-rank test. Results: A total of 46 patients were included. The median age was 62 years, and 29 were men. IR was continued for 698 (280, 1183) days before the conversion. During the last 3-month IR therapy, serum triglyceride levels remained unchanged from 171 (138, 239) mg/dL to 181 (123, 245) mg/dL (p = 0.78). Following the conversion, no patients had drug-related adverse events, and all patients completed 3-month XR therapy. At three months after the conversion, the serum triglyceride levels decreased significantly from 181 (123, 245) mg/dL to 146 (107, 184) mg/dL (p < 0.001). Conclusions: Pemafibrate XR might be a more promising medication than conventional IR in improving hypertriglyceridemia, probably due to improved medication adherence. [ABSTRACT FROM AUTHOR]

With the escalating prevalence of hair loss, the demand for effective hair loss treatment has surged. This study evaluated the effects of hot water extract of Hydrangea serrata (Thunb.) Ser. leaf (WHS) on hair growth, employing cell cultures, mice, and human skin organoid models. Both WHS and hydrangenol were found to enhance 5α-reductase inhibitory activity. WHS and hydrangenol have been shown to stimulate dermal papilla cell (DPC) growth, potentially through factors like keratinocyte growth factor (KGF), fibroblast growth factor 10 (FGF10), and transforming growth factor-β1 (TGF-β1). They also elevated the expression levels of keratin genes (K31 and K85) and the ceramide synthase (CerS3) gene, crucial clinical indicators of hair health. Furthermore, they exhibited notable anti-inflammatory and anti-androgenic properties by reducing the levels of tumor necrosis factor-α (TNF-α) and androgen signaling molecules, including androgen receptor (AR) and dickkopf-1 (DKK-1) gene expression. Oral administration of WHS to C57BL/6 mice for 3 weeks confirmed its hair growth-promoting effects, improving hair growth parameters and gene expression without significant changes in hair weight. Additionally, in a human skin organoid model, WHS was found to stimulate hair formation and augment the expression of follicle markers. These findings position WHS as a promising nutraceutical for promoting hair health, as evidenced by its efficacy in both in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aβ) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery. [ABSTRACT FROM AUTHOR]

In industrialized farms, rabbit does undergo intensive production rhythms which overlap lactation and gestation, leading to a high energy mobilization and increasing oxidative stress. Accordingly, we hypothesize that administration of the flavonoid quercetin (QUR) may improve the antioxidant status of young and adult rabbit reproductive females. In this study, the effect of daily oral administration of 300 mg/kg QUR for 8 weeks was assessed on the antioxidant profile of 24 New Zealand × Californian rabbit does, assigned to 4 experimental groups: rearing young (8–16 weeks old) and adult does at the end of their reproductive life (12–14 months old, with at least 3–4 reproductive cycles) treated (YQ and AQ) or not (YC and AC) with QUR, respectively. Plasma glutathione (GSH), as well as serum superoxide dismutase (SOD) and malondialdehyde (MDA) were measured during the experimental period. To assess the health status of the animals, a physical examination was also performed. GSH plasma concentrations were significantly higher in young does at weeks 1 and 4, but not at week 8 of the experiment, irrespectively of QUR administration. An increase in GSH plasma concentration was observed during the 8‐week experiment in both AQ and AC groups. Furthermore, QUR administration did not alter either SOD or MDA serum activity and concentration in any group during the experimental period. Physical examination revealed no differences between the experimental groups. In conclusion, under our experimental conditions, QUR did not modify the general clinical or the antioxidant profile of young and adult reproductive rabbit females. [ABSTRACT FROM AUTHOR]