Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

Psoralen Isolated from the Roots of Dorstenia psilurus Welw. Modulate Th1/Th2 Cytokines and Inflammatory Enzymes in LPS-Stimulated RAW 264.7 Macrophages.

Dorstenia psilurus is a widely used plant spice in traditional African medicine to treat pain-related conditions. However, the anti-inflammatory mechanisms underlying this activity and the main active ingredients of D. psilurus have not yet been fully characterized. This study aimed to isolate and identify the main active anti-inflammatory constituents of the D. psilurus extract and to investigate the underlying anti-inflammatory mechanisms in murine macrophages. Chromatographic techniques and spectroscopic data were used for compound isolation and structure elucidation. The Griess reagent method and the ferrous oxidation-xylenol orange assay were used to evaluate the inhibition of NO production and 15-lipoxygenase activity, respectively. Cyclooxygenase activity was assessed using the fluorometric COX activity assay kit, and Th1/Th2 cytokine measurement was performed using a flow cytometer. The results indicated that the extract and fractions of D. psilurus inhibit NO production and proliferation of RAW 264.7 macrophage cells. Bioguided fractionation led to the identification of psoralen, a furocoumarin, as the main bioactive anti-inflammatory compound. Psoralen inhibited NO production and 15-lipoxygenase activity and reduced pro-inflammatory Th1 cytokines (IFN-γ, TNF-α, and IL-2) while increasing the secretion of anti-inflammatory cytokines (IL-4, IL-6, and IL-10) in activated RAW 264.7 macrophage cells. The encouraging results obtained in this study suggest that psoralen-based multiple modulation strategies could be a useful approach to address the treatment of inflammatory diseases.

Item analysis: the impact of distractor efficiency on the difficulty index and discrimination power of multiple-choice items.

BACKGROUND: Distractor efficiency (DE) of multiple-choice questions (MCQs) responses is a component of the psychometric analysis used by the examiners to evaluate the distractors' credibility and functionality. This study was conducted to evaluate the impact of the DE on the difficulty and discrimination indices. METHODS: This cross-sectional study was conducted from April to June 2023. It utilizes the final exam of the Principles of Diseases Course with 45 s-year students. The exam consisted of 60 type A MCQs. Item analysis (IA) was generated to evaluate KR20, difficulty index (DIF), discrimination index (DIS), and distractor efficiency (DE). DIF was calculated as the percentage of examinees who scored the item correctly. DIS is an item's ability to discriminate between higher and lower 27% of examinees. For DE, any distractor selected by less than 5% is considered nonfunctional, and items were classified according to the non-functional distractors. The correlation and significance of variance between DIF, DI, and DE were evaluated. RESULTS: The total number of examinees was 45. The KR-20 of the exam was 0.91. The mean (M), and standard deviation (SD) of the DIF of the exam was 37.5(19.1), and the majority (69.5%) were of acceptable difficulty. The M (SD) of the DIS was 0.46 (0.22), which is excellent. Most items were excellent in discrimination (69.5%), only two were not discriminating (13.6%), and the rest were of acceptable power (16.9%). Items with excellent and good efficiency represent 37.3% each, while only 3.4% were of poor efficiency. The correlation between DE and DIF (p = 0.000, r= -0.548) indicates that items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and vice versa. The correlation between DE and DIS is significantly negative (P = 0.0476, r=-0.259). In such a correlation, items with efficient distractors are associated with low-discriminating items. CONCLUSIONS: There is a significant moderate negative correlation between DE and DIF (P = 0.00, r = -0.548) and a significant weak negative correlation between DE and DIS (P = 0.0476, r = -0.259). DIF has a non-significant negative correlation with DIS (P = 0.7124, r = -0.0492). DE impacts both DIF and DIS. Items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and discriminating items. Improving the quality of DE will decrease the number of NFDs and result in items with acceptable levels of difficulty index and discrimination power.

Prevalence and Comorbidities Among Individuals With Rheumatoid Arthritis in the Saudi Arabian Context.

BACKGROUND:  Rheumatoid arthritis (RA) in Saudi Arabia (SA) is a significant health concern with a notable impact on individuals and the healthcare system. This study aimed to investigate the prevalence and profile of comorbidities in patients with RA. METHODOLOGY:  This is a retrospective descriptive study involving 150 RA patients from August 2022 to August 2023, which was conducted at Khamis Mushait General Hospital, a major healthcare institution in SA. We examined the medical records to gather pertinent information. Stata Statistical Software: Release 18 (2023; StataCorp LLC, College Station, Texas, United States) was used for data analysis. The examination focused on sociodemographic factors, disease duration, prescribed medications (including methotrexate and biologic therapy), and the presence of comorbidities. Approval for the study was obtained from the Institutional Review Board of the Aseer Ministry of Health (approval number: H-06-B-091). RESULTS:  The study found a high prevalence of comorbidities in patients with RA. Around 96.7% of the patients had at least one documented comorbidity, highlighting this population's burden of additional health conditions. The most common comorbidity observed was anemia, affecting 48.7% of the patients. Other frequently observed comorbidities include hypertension, hyperlipidemia, diabetes mellitus, osteoporosis, interstitial lung disease, chronic renal disease, stroke, and coronary artery disease. The factors influencing comorbidities included an odds ratio of 1.086 (p=0.025), while being male was associated with lower odds (odds ratio=0.529, p=0.017). Additionally, disease duration (odds ratio=1.164, p=0.007), methotrexate use (odds ratio=2.553, p=0.001), and receiving biologic therapy (odds ratio=3.488, p<0.001) were significant contributors to comorbidities. CONCLUSION:  These findings highlight the need for comprehensive approaches to address RA and its associated comorbidities. Research and awareness initiatives are essential to understand better the specific nuances of RA in SA, leading to improved diagnostic and treatment strategies for the needs of the local population.

Awareness of Post-COVID-19 Syndrome Among the General Population of the Kingdom of Saudi Arabia.

Background Post-COVID-19 syndrome (PC19S) is an emerging pathological entity characterized by the development or persistence of a spectrum of symptoms and signs 12 weeks after the original disease. Most COVID-19 patients show a variety of persistent symptoms after recovery that impact their quality of life and professional performance. The prevalence of PC19S is found to be high among many populations hence, the need for knowledge and understanding of its risk factors, symptoms, and the awareness of the population about them to improve the provided health and medical care. Aim This study aims to assess the level of awareness of post-COVID-19 syndrome among the general population of the Kingdom of Saudi Arabia (KSA). Most studies have focused on hospitalized patients and those with severe disease, but PC19S can exist in other categories of COVID-19 patients; hence, the need for total population coverage. Methodology A cross-sectional study was conducted during the period between June 2023 and August 2023 using a structured self-administered online questionnaire. The online questionnaire in addition to the demographic characteristics consists of two main parts, one is about the awareness of the Saudi population of symptoms of PC19S and the other is about awareness of its risk factors. Results The majority of the participants (1558; 72.4%) showed low awareness of PC19S symptoms while only about one quarter (595; 27.6%) showed satisfactory awareness. Also, the awareness of the participants toward risk factors was low, as 1738 (80.7%) of them showed low awareness. We categorized the results into three levels of awareness to simplify and facilitate interpretation. The findings showed that 1380 individuals (64.09%) had low awareness of PC19S, 536 individuals (24.89%) had moderate awareness, and only 237 individuals (11%) had high awareness. The study reported that the highest awareness toward symptoms was of smell disturbances (1206; 56.0%) and the least was of hair loss (506; 23.5%) while among the risk factors, the highest was found toward old age 1326 (61.6%) and the female sex was the lowest 194 (9.0%). Conclusion The study revealed that the majority of the participants demonstrated low awareness of symptoms and risk factors, which needs a continuous effort to raise the population's awareness of this health-threatening condition.

miRNAs dysregulation in ankylosing spondylitis: A review of implications for disease mechanisms, and diagnostic markers.

Epigenetic processes, including non-coding RNA, histone modifications, and DNA methylation, play a vital role in connecting the environment to the development of a disorder, especially when there is a favorable genetic background. Ankylosing Spondylitis (AS) is a chronic type of spinal arthritis that highlights the significance of epigenetics in diseases related to autoimmunity and inflammation. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in both normal and aberrant pathological and physiological gene expression. This study focuses on the pathophysiological pathways to clarify the role of miRNAs in AS. We have conducted a thorough investigation of the involvement of miRNAs in several processes, including inflammation, the production of new bone, T-cell activity, and the regulation of pathways such as BMP, Wnt, and TGFß signaling. Undoubtedly, miRNAs play a crucial role in enhancing our comprehension of the pathophysiology of AS, and their promise as a therapeutic strategy is quickly expanding.

Awareness of Antibiotic Misuse in Upper Respiratory Tract Infections Among Adults in the Bisha Governorate in 2024.

INTRODUCTION: Antibiotics are targeted to kill or inhibit the growth of bacteria and have no effect on viral agents. Unfortunately, viruses cause about 80% of respiratory tract infections, and up to 75% of antibiotics are prescribed for URTIs. Overuse of antibiotics is linked to a number of issues, including the emergence of antibacterial resistance, an increase in the prevalence of chronic illnesses, a rise in the expense of healthcare services, and the emergence of side effects. This study aimed to assess the awareness of antibiotic misuse for URTIs among adults in the Bisha governorate in 2024. METHODS AND MATERIALS: A community-based, cross-sectional study was conducted in the Bisha governorate among the adult population. Data was collected using an online standardized self-administered adapted questionnaire. The questions vary from multiple choice to Likert scale questions, and each question has 2 points. Data was analyzed using SPSS version 26 (IBM SPSS Statistics, Armonk, NY). RESULTS: The response rate was about 85.3% (721/845). The ages of the participants ranged between 18 and 75 years. There were 360 (49.9%) male respondents and 361 (50.1%) female respondents. The study revealed that 83.1% (599) of the participants have poor awareness of antibiotic misuse in URTIs. Knowledge of antibiotic misuse consequences was poor at 66.7% (481). There was a significant difference observed between the residents of Bisha city compared to the residents of Bisha villages in total knowledge level about antibiotic misuse in URTIs (p = 0.030). CONCLUSION AND RECOMMENDATIONS: The population of the Bisha governorate has a poor knowledge of antibiotic misuse in URTIs. Therefore, efforts should be made to increase the knowledge and awareness of the general public about the problem.

The emerging role of miRNAs in myocardial infarction: From molecular signatures to therapeutic targets.

Globally, myocardial infarction (MI) and other cardiovascular illnesses have long been considered the top killers. Heart failure and mortality are the results of myocardial apoptosis, cardiomyocyte fibrosis, and cardiomyocyte hypertrophy, all of which are caused by MI. MicroRNAs (miRNAs) play a crucial regulatory function in the progression and advancement of heart disease following an MI. By consolidating the existing data on miRNAs, our aim is to gain a more comprehensive understanding of their role in the pathological progression of myocardial injury after MI and to identify potential crucial target pathways. Also included are the primary treatment modalities and their most recent developments. miRNAs have the ability to regulate both normal and pathological activity, including the key signaling pathways. As a result, they may exert medicinal benefits. This review presents a comprehensive analysis of the role of miRNAs in MI with a specific emphasis on their impact on the regeneration of cardiomyocytes and other forms of cell death, such as apoptosis, necrosis, and autophagy. Furthermore, the targets of pro- and anti-MI miRNAs are comparatively elucidated.

The Role of Pro-Inflammatory Chemokines CCL-1, 2, 4, and 5 in the Etiopathogenesis of Type 2 Diabetes Mellitus in Subjects from the Asir Region of Saudi Arabia: Correlation with Different Degrees of Obesity.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is becoming a major global health concern, especially in developing nations. The high prevalence of obesity and related diabetes cases are attributed to rapid economic progress, physical inactivity, the consumption of high-calorie foods, and changing lifestyles. OBJECTIVES: We investigated the roles of pro-inflammatory chemokines CCL1, 2, 4, and 5 in T2DM with varying levels of obesity in the Asir region of Saudi Arabia. MATERIALS AND METHODS: In total, 170 confirmed T2DM subjects and a normal control group were enrolled. Demographic data, serum levels of CCL-1, 2, 4, and 5, and biochemical indices were assessed in the subjects and control groups by standard procedures. RESULTS: T2DM subjects were divided into four groups: A (normal body weight), B (overweight), C (obese), and D (highly obese). We observed that male and female control subjects had similar mean serum concentrations of pro-inflammatory chemokines CCL-1, 2, 4, and 5. T2DM subjects in all the four groups showed significantly higher levels of all the four chemokines compared to the controls, regardless of gender. In T2DM subjects with obesity and severe obesity, the rise was most significant. There was a progressive rise in the concentrations of CCL-1, 2, and 4 in T2DM subjects with increasing BMI. Serum CCL5 levels increased significantly in all T2DM subject groups. The increase in CCL5 was more predominant in normal-weight people, compared to overweight and obese T2DM subjects. CONCLUSIONS: Male and female control subjects had similar serum levels of pro-inflammatory chemokines CCL-1, 2, 4, and 5. The progressive rise in blood concentrations of three pro-inflammatory chemokines CCL-1, 2, and 4 in T2DM subjects with increasing BMI supports the idea that dyslipidemia and obesity contribute to chronic inflammation and insulin resistance. Serum CCL5 levels increased significantly in all T2DM subject groups. The selective and more pronounced increase in CCL5 in the T2DM group with normal BMI, compared to subjects with varying degrees of obesity, was rather surprising. Further research is needed to determine if CCL5 underexpression in overweight and obese T2DM subjects is due to some unexplained counterbalancing processes.

Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib.

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer.

A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-ß, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.

Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach.

Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/ß-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.