pH-Sensitive blue and red N-CDs for L-asparaginase quantification in complex biological matrices.

A novel fluorometric method for the determination of L-asparaginase, an enzyme crucial in cancer therapy and food industry applications, is presented. This sensitive and selective approach utilizes L-asparagine and two pH-sensitive carbon dots (blue-N-CDs and red-N-CDs) as probes. The interaction between L-asparagine and L-asparaginase liberates ammonia, causing an increase in pH. This pH change simultaneously decreases the fluorescence of blue-N-CDs while enhancing the emission of red-N-CDs, enabling ratiometric detection of L-asparaginase. Comprehensive characterization of both carbon dots and investigation of their response mechanism towards L-asparaginase were conducted using ultraviolet-visible spectrophotometry, fluorescence spectroscopy, and transmission electron microscopy (TEM) imaging techniques. The designed approach demonstrates outstanding linearity (20 to 2000 U L-1) and a low detection limit (6.95 U L-1) for L-asparaginase quantification. Moreover, when tested to human serum samples, the detection system exhibits outstanding selectivity and high recovery rates (96.15% to 99.75%) with low standard deviation, underscoring its suitability for practical implementation in clinical diagnostics.

L-asparaginase-mediated pH shift and carbon dot fluorescence modulation: A sensitive ratiometric method for quantifying L-asparagine in diverse potato varieties under variable storage conditions.

This study presents a novel and selective method for the determination of l-asparagine in diverse potato varieties under various storage conditions. L-asparagine levels serve as a crucial indicator for acrylamide formation, a hazardous substance in processed potato products. The fluorometric method utilized blue-emitting CDs (B-CDs), orange-emitting CDs (O-CDs), and the enzyme L-asparaginase for ratiometric detection of L-asparagine. Upon enzymatic hydrolysis of L-asparagine by L-asparaginase, liberated ammonia induced a pH increase in the reaction medium. This pH shift enhanced the fluorescence of B-CDs while simultaneously decreasing that of O-CDs, enabling sensitive and selective L-asparagine quantification. Comprehensive characterization of the CDs was performed using various spectroscopic techniques and transmission electron microscopy. The method demonstrated excellent sensitivity (LOD = 0.31 µM) and a wide linear range (1.0-50.0 µM). When the method was applied to potato samples, high recovery values (98.00-100.33 %) with low relative standard deviations (RSDs) were achieved, confirming the accuracy and precision of the method. The approach was employed to determine L-asparagine levels in three potato varieties (Lady Rosetta, Spunta, and Nicola) under different storage temperatures and durations. This method provides a valuable tool for monitoring L-asparagine content in potatoes, potentially aiding in the mitigation of acrylamide formation during processing. The robust performance and simplicity of the proposed technique make it suitable for routine analysis in both research and industrial applications within the potato industry.

Electrochemical determination of captopril using a disposable graphite electrode modified with a molecularly imprinted film, accompanied by a ratiometric read-out.

In this research paper, a novel "signal on-off" ratiometric-based electrochemical platform was developed for the sensitive and selective detection of captopril. Ratiometric responses were achieved by fabricating molecularly imprinted polymers (MIPs) on the surface of a graphite electrode (GE) decorated with nitrogen (N) and sulfur (S) co-doped porous carbon and silver nanoparticles (Ag). The MIP layer was formed via electropolymerization of copper coordinated with pyrrole-3-carboxylic acid (functional monomer). Silver nanoparticles (Ag) were incorporated to enhance conductivity and surface area and to serve as an internal reference output. Upon the addition of captopril, there was a decrease in the anodic oxidation current of Ag+ at around 0.067 V, coupled with an increase in the oxidation current at 0.54 V (Ag-captopril complex). Under optimized conditions, the electrochemical responses (IAg-captopril/IAg) increased linearly with increasing captopril concentration in the range of 1-450 nM, with a detection limit (S/N = 3) of 0.3 nM. The ratiometric-based MIP electrochemical platform (Cu-MIP/NS-PC@Ag/GE) was successfully applied to detect captopril in complex matrices such as tablets, serum, and urine samples. This platform holds promise for sensitive and selective detection of captopril in various practical applications.

A bench-top evaluation of the Ily® robotics assisted tele console system in ureteroscopy by medical students, residents and urologists: does prior videogaming experience help shape the learning curve?

PURPOSE: Previous studies have demonstrated an association between video-gaming experience (VGE) and improved robotics skills. We aimed to evaluate the initial learning curve for the Ily® robotics system (Sterlab, Sophia Antipolis, France) when applied to flexible ureteroscopy (FU) among both medical students and urology surgeons. METHODS: There were two groups, surgeons and students. An initial questionnaire was completed detailing basic demographics and experience. In part one, both groups performed two simple timed tasks using an Ily® mounted single-use RAU. In part two, group 1 repeated both tasks using a hand-held FU. A subjective assessment of comfort, intuitiveness and a NASA Task Load Index were then completed. RESULTS: There was a total of 28 participants. Among medical students with VGE (n = 9, 64%)., average calyceal inspection time was 185 ± 80 s; 133 ± 42 s; 121 ± 71 s. For non-gamers (n = 5, 36%), average times were longer at 221 ± 97 s; 134 ± 35 s; 143 ± 68 s respectively. Average calyceal inspection time for videogaming surgeons (n = 8, 57%) was 126 ± 95 s; 98 ± 40 s; 107 ± 71 s, respectively. For non-gamers average inspection times were longer at 150 ± 73 s; 114 ± 82 s; 111 ± 47 s, respectively. None of these differences achieved statistical significance. Surgeons trial speeds were, however, significantly faster by hand-held compared to RAU: by 103, 81 and 82 s respectively (p < 0.05). CONCLUSION: These results show that ex- or current- video gamers do not have a significant advantage in time to perform FU. Any early advantage conferred to ex- or current- gamers may be rapidly overcome.

Closing the loop: Strengthening course quality of Pharm.D. program via applying a comprehensive four-step review approach.

This study explores the course review process implemented by the College of Pharmacy at King Saud University for its Pharm.D. program. Through a qualitative research design, a dedicated course review committee was established to oversee the evaluation process. The committee gathered and analyzed data from various sources, including course reports, student evaluations, and exam center reports, to achieve a holistic understanding of each course's effectiveness. The evaluation process was structured into a Four-Step Course Evaluation Approach: data collection, data review and recommendations, taking appropriate action, and communicating the outcomes. The "closing the loop" stage ensured that recommendations were effectively implemented, and course evaluation data were systematically archived for future reference. The results of this study, based on the evaluation of 25 courses, revealed significant improvements in course quality, alignment with program learning outcomes, and adherence to accreditation standards. Key findings included the identification of gaps and discrepancies, leading to targeted interventions and enhanced course content. Overall, this study highlights the effectiveness of a structured course review process in enhancing the quality of education and ensuring continuous improvement within the college. The committee focuses on refining evaluation criteria, conducting workshops, and providing training to stay current with emerging accreditation standards and best practices. This systematic course review process demonstrates the College's commitment to providing high-quality education and preparing students for successful careers in pharmacy, with significant implications for the improvement of pharmacy education and the overall student learning experience.

A novel urease-assisted ratiometric fluorescence sensing platform based on pH-modulated copper-quenched near-infrared carbon dots and methyl red-quenched red carbon dots for selective urea monitoring.

A novel and sensitive fluorescence ratiometric method is developed for urea detection based  on the pH-sensitive response of two fluorescent carbon dot (CD) systems: R-CDs/methyl red (MR) and NIR-CDs/Cu2+. The sensing mechanism involves breaking down urea using the enzyme urease, releasing ammonia and increasing pH. At higher pH, the fluorescence of NIR-CDs is quenched due to the enhanced interaction with Cu2+, while the fluorescence of R-CDs is restored as the acidic MR converts to its basic form, removing the inner filter effect. The ratiometric signal (F608/F750) of the R-CDs/MR and NIR-CDs/Cu2+ intensities changed in response to the pH induced by urea hydrolysis, enabling selective and sensitive urea detection. Detailed spectroscopic and morphological investigations confirmed the fluorescence probe design and elucidated the sensing mechanism. The method exhibited excellent sensitivity (0.00028 mM LOD) and linearity range (0.001 - 8.0 mM) for urea detection, with successful application in milk samples for monitoring adulteration, demonstrating negligible interference and high recovery levels (96.5% to 101.0%). This ratiometric fluorescence approach offers a robust strategy for selective urea sensing in complicated matrices.

A Culture of Early Mobilization in Adult Intensive Care Units: Perspective and Competency of Physicians.

BACKGROUND: Early mobility (EM) is vital in the intensive care unit (ICU) to counteract immobility-related effects. A multidisciplinary approach is key, as it requires precise initiation knowledge. However, physicians' understanding of EM in adult ICU settings remains unexplored. This study was conducted to investigate the knowledge and clinical competency of physicians working in adult ICUs toward EM. METHODS: This cross-sectional study enrolled 236 physicians to assess their knowledge of EM. A rigorously designed survey comprising 30 questions across the demographic, theoretical, and clinical domains was employed. The criteria for knowledge and competency were aligned with the minimum passing score (70%) stipulated for physician licensure by the medical regulatory authority in Saudi Arabia. RESULTS: Nearly 40% of the respondents had more than 5 years of experience. One-third of the respondents received theoretical knowledge about EM as part of their residency training, and only 4% of the respondents attended formal courses to enhance their knowledge. Almost all the respondents (95%) stated their awareness of EM benefits and its indications and contraindications and considered it safe to mobilize patients on mechanical ventilators. However, 62.3% of the respondents did not support EM for critically ill patients on mechanical ventilators until weaning. In contrast, 51.7% of respondents advised EM for agitated patients with RASS > 2. Only 113 (47.9%) physicians were competent in determining the suitability of ICU patients for EM. For critically ill patients who should be mobilized, nearly 60% of physicians refused to initiate EM. CONCLUSIONS: This study underscores insufficient practical knowledge of ICU physicians about EM criteria, which leads to suboptimal decisions, particularly in complex ICU cases. These findings emphasize the need for enhanced training and education of physicians working in adult ICU settings to optimize patient care and outcomes in critical care settings.

A novel disposable ultrasensitive sensor based on nanosized ceria uniformly loaded carbon nanofiber nanoceramic film wrapped on pencil graphite rods for electrocatalytic monitoring of a tyrosine kinase inhibitor capmatinib.

For the first time, we introduce a novel disposable and ultrasensitive sensing electrode made up of nanosized ceria uniformly loaded carbon nanofibers (CeNPs@CNF) sol-gel nanoceramic film (CF) wrapped on eco-friendly and inexpensive pencil graphite rods (PGRs) to explore their electro-catalytic detection of the anticancer drug capmatinib (CMB). The as-prepared CeNPs@CNF hybrid nanocomposite was described by XRD, SEM, TEM, HRTEM, and EDX analysis. The CV study clearly demonstrated that, the disposable CeNPs@CNF-CF/PGRE sensor exhibited excellent redox activities in the ideal probe [Fe(CN)6]3-/4-. Due to the outstanding electrochemical properties, larger electrochemically active surface area, and tremendous electro-catalytic activity of CeNPs@CNF, the reduction current of CMB on the CeNPs@CNF-CF/PGRE sensor is considerably higher than that of bare PGRE. The detection conditions, such as supporting electrolyte, pH of the buffer solution, amount of modifier, adsorption potential, and time, were studied and optimized. The sensing platform demonstrated high sensitivity (1.2 µA nM-1 cm-2), an ultralow detection limit (0.6 nM), and a wide linear range of 2.0 nM-400 nM of CMB compared to the bare PGRE. Additionally, the CeNPs@CNF-CF/PGRE sensor showed high selectivity, stability, and simple operation, which provided a promising alternative tool for fast detection of CMB in human body fluids with good recoveries.

DNMT inhibitor, 5-aza-2'-deoxycytidine mitigates di(2-ethylhexyl) phthalate-induced aggravation of psoriasiform inflammation in mice via reduction in global DNA methylation in dermal and peripheral compartments.

Psoriasis is classified as an autoimmune disorder characterized by abnormal immune response leading to the development of chronic dermal inflammation. Most individuals have a genetic vulnerability that may be further influenced by epigenetic changes occurring due to multiple variables such as pollutant exposure. Epigenetic modifications such as DNA methylation possess a dynamic nature, enabling cellular differentiation and adaptation by controlling gene expression. Di(2-ethylhexyl) phthalate (DEHP) and psoriatic inflammation are known to cause modification of DNA methylation via DNA methyltransferase (DNMT). However, it is not known whether DEHP, a ubiquitous plasticizer affects psoriatic inflammation via DNMT modulation. Therefore, this study investigated the effect of DNMT inhibitor, 5-aza-2'-deoxycytidine (AZA) on DEHP-induced changes in the expression of DNMT1, global DNA methylation, and anti-/inflammatory parameters (p-STAT3, IL-17A, IL-6, iNOS, IL-10, Foxp3, Nrf2, HO-1) in the skin and the peripheral adaptive/ myeloid immune cells (CD4+ T cells/CD11b+ cells) in imiquimod (IMQ) model of psoriasiform inflammation. Further, psoriasis-associated clinical/histopathological features (ear thickness, ear weight, ear PASI score, MPO activity, and H&E staining of the ear and the back skin) were also analyzed in IMQ model. Our data show that IMQ-treated mice with DEHP exposure had increased DNMT1 expression and DNA methylation which was associated with elevated inflammatory (p-STAT3, IL-17A, IL-6, iNOS) and downregulated anti-inflammatory mediators (IL-10, Foxp3, Nrf2, HO-1) in the peripheral immune cells (CD4+ T cells/CD11b+ cells) and the skin as compared to IMQ-treated mice. Treatment with DNMT1 inhibitor caused reduction in inflammatory and elevation in anti-inflammatory parameters with significant improvement in clinical/histopathological symptoms in both IMQ-treated and DEHP-exposed IMQ-treated mice. In conclusion, our study shows strong evidence indicating that DNMT1 plays an important role in DEHP-induced exacerbation of psoriasiform inflammation in mice through hypermethylation of DNA.

Characterization of Demographic, Clinical, and Laboratory Risk Factors for Stroke in a Tertiary Hospital in Riyadh, Saudi Arabia.

Background Stroke is a major cause of death and long-term disability worldwide, with varying incidence and risk factors across different populations. This study aims to analyze demographic, clinical, and laboratory risk factors for stroke among the Saudi Arabian population to enhance the understanding of its behavior and associated mortality. Methods In this retrospective cohort study, we analyzed data from 3586 patients diagnosed with hemorrhagic or non-hemorrhagic stroke at King Fahad Medical City from January 1, 2020, to November 11, 2022. We collected data on demographic variables, past medical history, social history, nationality, and laboratory components. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0. (Armonk, NY: IBM Corp.), with significance set at p<0.05. Results The study population was predominantly male (57.86%) and within the age group of 51 to 80 years (58.8%). A significant portion of patients were Saudi nationals (99.6%), with hypertension (50.2%) and diabetes (40.4%) being the most common comorbidities. Laboratory abnormalities related to sodium and potassium levels were strongly linked to mortality rates. Notably, ischemic stroke was the most common type across all age groups, except for patients under age 16, where hemorrhagic stroke was more prevalent. Conclusions Our findings reveal significant associations between stroke risk factors and mortality within the Saudi Arabian population, highlighting the impact of hypertension, diabetes, and electrolyte imbalances. The study underscores the need for targeted stroke prevention and management strategies in Saudi Arabia, aligning with global trends to mitigate the burden of this disease.

Healthcare Providers' knowledge, attitudes and practice in relation to drug hypersensitivity reactions at King Abdulaziz Medical City in Riyadh.

Background: Drug hypersensitivity reactions (DHRs) are immune-mediated responses triggered by exposure to a drug. DHRs are responsible for serious adverse drug reactions (ADRs) and are considered the fifth leading cause of death. This study aims to assess and evaluate the knowledge, practice, and attitudes of healthcare providers (HCPs) towards DHRs. Methods: A cross-sectional survey was conducted at King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. Healthcare providers, including pharmacists, physicians, and nurses, were recruited using a convenience sampling method to complete the survey. The survey comprised three domains: knowledge (14 items), attitudes (5 items), and practices (6 items), utilizing a standardized self-administered questionnaire. Results: The survey was completed by 373 healthcare providers. The respondents were predominantly female (72.1 %) with a mean age of 33.8 ± 7.8 years. Of the respondents, 64 % were nurses, 25 % pharmacists, and 11.3 % physicians. Educational levels varied, with 53 % holding a bachelor's degree, 22 % an associate degree, and 25 % a master's degree or higher. The median knowledge score was 48. Female healthcare providers, those with advanced levels of education, and physicians had higher knowledge scores compared to male and nurse participants (p < 0.05). One-third of the respondents (33 %) were satisfied with their knowledge of DHRs, and 42 % believed HCPs should receive more advanced training in DHR management. Less than a quarter of HCPs reported inquiring about patients' histories of hypersensitivity reactions. Conclusions: The study revealed that healthcare workers had a relatively low level of knowledge about drug hypersensitivity reactions and lacked a consensus on DHR management. While displaying a positive attitude towards DHRs, they often did not translate this attitude into consistent clinical practice.

Exploring the Enigmatic Link: Unraveling the Relationship Between Obesity and Cigarette Smoking Among Diverse College Students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia.

BACKGROUND: Obesity is defined as an excess of body fat. This medical condition frequently results in a high BMI and an increased risk of a variety of health problems, including diabetes, cardiovascular disease, and certain types of cancer. Cigarette smoking includes inhaling smoke created by the combustion of tobacco. It is linked to a variety of health issues, including lung cancer, heart disease, and respiratory ailments, and is a primary cause of preventable disease and premature death worldwide. The association between obesity and cigarette smoking is complex and incompletely understood. This study aims to investigate the intriguing association between obesity and cigarette smoking among diverse college students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia. METHODOLOGY: The study was conducted as an observational study, specifically an analytical cross-sectional study, to measure the prevalence of cigarette smoking and obesity and their association. This type of study is chosen because of its advantages including targeting a large sample in a short time and inexpensive way, with no loss to follow-up, unlike some other study designs. RESULTS: In this study, we were able to collect data from 603 participants, of which 57.4% were male and 67.8% of them aged between 20 and 24 years old. Moreover, we found that 39.6% had normal weight; however, the prevalence of obesity, overweight, and underweight were 24%, 28.1%, and 8.3%, respectively. Considering the prevalence of smoking, we found that 22.6% of the participants reported being current smokers, while 5.3% were former smokers. There is a significant difference between participants with different BMIs (P=0.001). The prevalence of smoking was significantly higher in obese and overweighted participants (35.1% and 31.3%, respectively) compared with 28.4% in normal-weighted participants. CONCLUSION: The prevalence of smoking and obesity in this study was significantly higher than reported in different studies. Moreover, we found a significant relationship between smoking and obesity; however, further investigation should be conducted to determine the cause of this relationship.

Cobalt-modulated dual emission carbon dots for ratiometric fluorescent vancomycin detection.

This work presents a simple yet selective fluorometric protocol for the quantification of vancomycin, an important antibiotic for treating infections caused by Gram-positive bacteria. A novel ratiometric fluorometric method for the determination of vancomycin is developed based on dual emissive carbon dots (DECDs) with emission at 382 nm and 570 nm in combination with Co2+ ions. Upon addition of Co2+ions, the fluorescence at 382 nm of DECDs is enhanced while emission at 570 nm remains constant. In the presence of vancomycin, it complexes with Co2+ leading to quenching of the 382 nm fluorescence due to strong binding with Co2+ in the Co@DECDs system. The DECDs are fully characterized by TEM and different spectroscopic techniques. The proposed ratiometric method is based on measuring fluorescence ratio (F570/F382) against vancomycin concentration and the method exhibits a good linearity range from 0.0 to 120.0 ng mL-1 with a low limit of detection (S/N = 3) of 0.31 ng mL-1. The method shows good selectivity with minimal interference from potential interfering species. This ratiometric fluorometric approach provides a promising tool for sensitive and specific vancomycin detection in clinical applications.

Genetic variants associated with dengue hemorrhagic fever. A systematic review and meta-analysis.

Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations play a crucial role in influencing susceptibility to DHF. Therefore, this investigation conducted a meta-analysis to uncover genetic changes that might have remained undetected in individual studies due to small sample sizes or methodological differences. Among 2212 initially identified studies, 23 were deemed suitable for analysis based on PRISMA guidelines. Toll-like receptors (TLR) and CD209 showed significant association with DHF (odds ratios: TLR=0.56, CD209 =0.55), indicating protective effects. However, tumor necrosis factor (TNF) and human leukocyte antigen (HLA) did not exhibit a statistically significant relationship with DHF. This study emphasizes the relevance of TLR and CD209 in DHF susceptibility and resistance across diverse geographical locations.

The effect of inhibiting hindbrain A2 noradrenergic neurons by 6-Hydroxydopamine on lipopolysaccharide-treated male rats autistic animal model.

Autism spectrum disorder (ASD) is a complex neurodevelopmental illness that often emerges in early childhood. The incidence of ASD has shown a notable rise in recent years. ASD is defined by deficits in social communication, and presence of rigid and repetitive behaviors and interests. The underlying mechanisms of ASD remain elusive. Multiple studies have documented the presence of neuroinflammation and increased levels of inflammatory cytokines, specifically, IL-6, TNF, and NF-κB, in various brain regions, including the prefrontal cortex (PFC) and hippocampus in individuals with ASD. Noradrenergic neurons play a crucial role in brain development and the regulation of motor, behavioral, and memory functions. This study sought to examine the impact of intracerebroventricular (icv.) injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), in the caudal dorsal vagal complex A2 neurons on various neuroinflammatory pathways at the hippocampus and PFC in valproic acid (VPA) autistic animal model. This was done in conjunction with an intraperitoneal (i.p.) injection of Lipopolysaccharides (LPS) in animal models with VPA-induced autism. We specifically examined the impact of the caudal fourth ventricle 6-OHDA icv. injection and LPS (i.p.) injection on self-grooming behavior. We measured the mRNA expression of IL-6, TNF-a, and NF-κB using qRT-PCR, and the protein expression of COX-2, GPX-1, p-AMPK, and AMPK using western blot analysis. The self-grooming activity was considerably higher in the combined treatment group (6-OHDA icv. + LPS i.p.) compared to the control group. A substantial increase observed in the expression of IL-6, TNF-α, and NF-κB genes in the PFC of the treatment group that received icv. Administration of 6-OHDA, compared to the control group. The VPA-autism rats that received the combo treatment exhibited a slight increase in the expression level of NF-κB gene in the hippocampus, compared to the control group. At the PFC, we noticed a substantial drop in the expression of the antioxidant protein GPX-1 in the group that received the combo treatment compared to the control group. Our data investigates a novel aspect that the 6-OHDA-induced inhibition of hindbrain A2 neurons could be influencing the neuroinflammatory pathways in the PFC and hippocampus of autistic animal models.

Selective fluorescence turn-on detection of combination cisplatin-etoposide chemotherapy based on N-CDs/GSH-CuNCs nanoprobe.

Cisplatin (CIS) and etoposide (ETP) combination therapy is highly effective for treating various cancers. However, the potential for pharmacokinetic interactions between these drugs necessitates selective sensing methods to quantitate both CIS and ETP levels in patient's plasma. This work develops a dual fluorescence probe strategy using glutathione-capped copper nanoclusters (GSH-CuNCs) and nitrogen-doped carbon dots (N-CDs) for the simultaneous analysis of CIS and ETP. The fluorescence signal of GSH-CuNCs at 615 nm increased linearly with CIS concentration while the N-CD emission at 480 nm remained unaffected. Conversely, the N-CD fluorescence was selectively enhanced by ETP with no interference with the CuNC fluorescence. Extensive materials characterization including UV-vis, fluorescence spectroscopy, XRD, and TEM confirmed the synthesis of the nanoprobes. The sensor showed high sensitivity with limits of detection of 6.95 ng mL-1 for CIS and 7.63 ng mL-1 for ETP along with excellent selectivity against potential interferences in rabbit plasma. Method feasibility was demonstrated with application to real rabbit plasma samples. The method was further applied to estimate the pharmacokinetic parameters of CIS before and after ETP coadministration. The dual nanoprobe sensing strategy enables rapid and selective quantitation of CIS and ETP levels to facilitate therapeutic drug monitoring and optimization of combination chemotherapy regimens.

Worsening of imiquimod-induced psoriasiform inflammation in mice by environmental pollutant, di-(2-ethylhexyl) phthalate through dysregulation in IL-17A and Nrf2/iNOS signaling in peripheral myeloid and CD4 + T cells.

Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic inflammation in myeloid cells (IL-6, IL-17A, IL-23), Th17 (p-STAT3, IL-17A, IL-23R, TNF-α), Th1 (IFN-γ), Treg (Foxp3, IL-10), and Nrf2/iNOS signaling in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our study showed increased Th17 signaling in imiquimod model which was further aggravated by DEHP exposure. Further, Nrf2 and iNOS signaling were also elevated in IMQ model where DEHP exposure further increased iNOS expression but did not modify the Nrf2 expression. Most importantly, IL-17A levels were also elevated in myeloid cells along with IL-6 which were further elevated by DEHP exposure. Overall, this study shows that IL-17A signaling is upregulated, whereas there is deficiency of Nrf2/HO-1 signaling by DEHP exposure in mice with psoriasiform inflammation. These observations suggest that DEHP aggravates IL-17A-mediated signaling both in CD4 + T cells as well as myeloid cells which is linked to exacerbation of IMQ-induced psoriatic inflammation in mice. Strategies that counteract the effect of DEHP exposure in the context of psoriatic inflammation through downregulation of IL-17A may be fruitful.

The Association of Psoriasis, Diabetes Mellitus, and Hypertension: A Meta-Analysis.

Psoriasis is a systemic disease affecting various organs; however, it is usually thought of as a skin disease. A multidisciplinary approach is needed for better outcomes. The current meta-analysis assessed the association between diabetes mellitus, high blood pressure, and psoriasis. We searched four databases, including Cochrane Library, PubMed, MEDLINE, and Google Scholar, for relevant articles using the following keywords: psoriasis, hypertension, high blood pressure, cardiovascular risk factors, and diabetes mellitus. The author's name, year, and country of publication, diabetes, and hypertension among patients with psoriasis and control subjects were collected and entered into a Microsoft Excel sheet. Out of 1209 articles retrieved, 903 articles remained after duplication removal. From the 82 full texts screened, only seven studies fulfilled the inclusion and exclusion criteria. Psoriasis was associated with diabetes and hypertension: odds ratio 1.38, 95% CI 1.17-1.64; P-value 0.0002, chi-square 224.93, and odds ratio 1.60, 95% CI 1.41-1.81, P-value 0.00001, chi-square 226.59, respectively. Substantial heterogeneity was observed (I2 for heterogeneity, 97%, P < 0.001). A broad approach is needed to address the associated comorbidities and select the appropriate therapeutic approach. Randomized controlled trials investigating the best drugs for the treatment of psoriasis and its associated cardiovascular risk factors are needed.

The Cross Talk Between Psoriasis, Obesity, and Dyslipidemia: A Meta-Analysis.

Although psoriasis is a multi-organ disease, it is usually managed as a skin disease, ignoring its associated serious comorbidities. This meta-analysis aimed to investigate the relationship between psoriasis, dyslipidemia, and obesity. Two authors independently searched three databases (PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), The Cochrane Library, and Google Scholar). The search was set for articles published in the English language during the period from January 2013 to August 2023. The keywords "psoriasis", "hypercholesterolemia", "dyslipidemia", "low-density lipoproteins", "high body mass index", and "obesity", were used. Out of the 145 full texts reviewed, only seven studies fulfilled the inclusion and exclusion criteria (773,761 participants and 196,593 events). Psoriasis was associated with dyslipidemia and obesity (odds ratio (OR)=1.63, 95% CI: 1.42-1.88 and OR=1.70, 95% CI: 1.43-2.02), respectively, with significant heterogeneity (98% and 97%, respectively). Dyslipidemia and obesity were significant psoriasis comorbidities; a broader approach, viewing psoriasis as a multi-organ disease, is recommended for optimal treatment and outcomes.

Examining the Effects of Dasatinib, Sorafenib, and Nilotinib on Vascular Smooth Muscle Cells: Insights into Proliferation, Migration, and Gene Expression Dynamics.

BACKGROUND: Dasatinib, nilotinib, and sorafenib are clinically proven tyrosine kinase inhibitors (TKIs) used for the treatment of leukemia and hepatocellular carcinoma. However, there is a growing concern regarding cardiotoxicity associated with their use. The impact of these TKIs on vascular smooth muscle cells (VSMCs) remains unexplored. This study aims to investigate the effects of TKIs on VSMC proliferation and migration, as well as to elucidate the underlying mechanisms involving inflammatory and apoptotic pathways. METHODS: VSMCs were extracted from albino rats and cultured in vitro. The cells were divided into four experimental groups: control, dasatinib, sorafenib, and nilotinib. The MTT assay was employed to assess the cytotoxic effects of TKIs on VSMCs. A scratch assay was conducted to evaluate the inhibitory potential of TKIs on VSMC migration. Flow cytometry analysis was used to detect apoptotic cells. Real-Time PCR expression was utilized to determine the differential gene expression of apoptotic and inflammatory markers. RESULTS: Dasatinib, nilotinib, and sorafenib demonstrated significant inhibitory effects on VSMC viability and migration at low concentrations (<1 µmol/L, p < 0.05). Furthermore, gene expression analysis revealed up-regulation of inflammatory biomarkers (TNF-α, IL-6, and IL-1ß) and apoptotic markers (P53, BAX), along with down-regulation of the anti-apoptotic biomarker BCL-2 in response to all TKIs. CONCLUSIONS: This study demonstrates that dasatinib, nilotinib, and sorafenib inhibit VSMC proliferation and migration, suggesting their potential to induce vascular injury and remodeling by activating inflammation and apoptosis pathways. These findings highlight the need for further investigation into the cardiotoxic effects of these TKIs and the development of strategies to mitigate their adverse vascular effects.