Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Patterns distribution, concentrations and sources of radioactive elements from black sand in the Red Sea coast, Egypt.

In Egypt, the distribution of black sand in various coastal regions has been readily apparent by thorough research. Unfortunately, these investigations did not measure radioactivity in black sand, particularly in the vicinity of the Red Sea. Gamma-ray spectroscopy was used to detect the naturally occurring radioactivity from 238U, 232Th, 40K, and 226Ra in black sand samples from eight locations along the Red Sea coast: Ras Elbehar, Gemsa, Hurghada Elahiaa, Hurghada Titanic, Safaga, Qusier Elsharm Alqbly, Gabal Alrosass, and Marsa Alam. The resultant data were interpolated to represent the spatial distribution. Additionally, the potential rocks sources of radionuclides were geologically mapped to elucidate the relationship between rock components and radioactivity. The results showed that 226Ra, 232Th and238U were higher at samples collected from Ras Elbehar, Hurghada Elahiaa and Hurghada Titanic compared to the other sites. On the other hand, 40K showed the lowest mean value (75.3 ± 3.8 Bq/kg) in Hurghada Titanic samples, while it peaked (563 ± 28 Bq/kg) in Qusier Elsharm Alqbly samples. The interpolated results show notable differences in radioactive amounts between the north and south, which are indicative of several environmental conditions and human activities. Alkaline syenite, syenogranite, older granites (tonalite and granodiorite), and minor acidic volcanic/metavolcanic rocks make up the upstream area of the basin area draining into, for example, the Ras Elbehar locality (highest activity concentrations for 238U (1596 ± 80 Bq/kg) and 226Ra (886 ± 44 Bq/kg)), while alkali-feldspar granite, schist, and shale rocks make up the mid-stream area. The findings provide a basis for scientific forecasting on the impact of synthetic or naturally occurring radioactive isotopes introduced into aquatic environments.

Immediate Versus Staged Complete Revascularization for Patients With ST-Segment-Elevation Myocardial Infarction and Multivessel Disease: A Network Meta-Analysis of Randomized Trials.

BACKGROUND: The comparative outcomes with immediate, staged in-hospital, and staged out-of-hospital complete revascularization for patients with ST-segment-elevation myocardial infarction and multivessel disease remain unclear. METHODS AND RESULTS: An electronic search of MEDLINE, SCOPUS, and Cochrane databases was performed through August 2023 for randomized trials evaluating immediate, staged in-hospital, and staged out-of-hospital complete revascularization for patients with ST-segment-elevation myocardial infarction and multivessel disease. The primary outcome was major adverse cardiac events (MACEs). The final analysis included 9 trials with 4270 patients. The weighted follow-up duration was 13.8 months. On pairwise meta-analysis, there were no statistically significant differences between immediate versus staged nonculprit percutaneous coronary intervention (PCI) in MACEs (odds ratio, 0.79 [95% CI, 0.54-1.16]). Network meta-analysis showed that there was no statistically significant difference in MACEs with staged in-hospital nonculprit PCI (odds ratio, 1.29-[95% CI, 0.91-1.82]) compared with immediate nonculprit PCI, while there were higher odds of MACEs with out-of-hospital nonculprit PCI (odds ratio, 1.67-[95% CI, 1.21-2.30]) compared with immediate nonculprit PCI. Compared with immediate nonculprit PCI, there were higher odds of ischemia-driven repeat revascularization with staged out-of-hospital nonculprit PCI (odds ratio, 2.26-[95% CI, 1.37-3.72]), but not with in-hospital staged nonculprit PCI. There were no significant differences for the other outcomes among the 3 strategies. CONCLUSIONS: Among patients with ST-segment-elevation myocardial infarction with multivessel disease, an immediate nonculprit PCI approach was associated with similar clinical outcomes to the staged nonculprit PCI approach. The staged out-of-hospital nonculprit PCI approach was associated with a higher incidence of MACEs compared with the other strategies, which was driven by higher risk for ischemia-driven repeat revascularization.

STA-9090 in combination with a statin exerts enhanced protective effects in rats fed a high-fat diet and exposed to diethylnitrosamine and thioacetamide.

Introduction: Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. Methods: We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. Results: HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression. Discussion: Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need.

IL-6 deficiency accelerates cerebral cryptococcosis and alters glial cell responses.

Cryptococcus neoformans (Cn) is an opportunistic encapsulated fungal pathogen that causes life-threatening meningoencephalitis in immunosuppressed individuals. Since IL-6 is important for blood-brain barrier support and its deficiency has been shown to facilitate Cn brain invasion, we investigated the impact of IL-6 on systemic Cn infection in vivo, focusing on central nervous system (CNS) colonization and glial responses, specifically microglia and astrocytes. IL-6 knock-out (IL-6-/-) mice showed faster mortality than C57BL/6 (Wild-type) and IL-6-/- supplemented with recombinant IL-6 (rIL-6; 40 pg/g/day) mice. Despite showing early lung inflammation but no major histological differences in pulmonary cryptococcosis progression among the experimental groups, IL-6-/- mice had significantly higher blood and brain tissue fungal burden at 7-days post infection. Exposure of cryptococci to rIL-6 in vitro increased capsule growth. In addition, IL-6-/- brains were characterized by an increased dystrophic microglia number during Cn infection, which are associated with neurodegeneration and senescence. In contrast, the brains of IL-6-producing or -supplemented mice displayed high numbers of activated and phagocytic microglia, which are related to a stronger anti-cryptococcal response or tissue repair. Likewise, culture of rIL-6 with microglia-like cells promoted high fungal phagocytosis and killing, whereas IL-6 silencing in microglia decreased fungal phagocytosis. Lastly, astrogliosis was high and moderate in infected brains removed from Wild-type and IL-6-/- supplemented with rIL-6 animals, respectively, while minimal astrogliosis was observed in IL-6-/- tissue, highlighting the potential of astrocytes in containing and combating cryptococcal infection. Our findings suggest a critical role for IL-6 in Cn CNS dissemination, neurocryptococcosis development, and host defense.

Correlation of silent brain infarcts and leukoaraiosis in middle-aged ischemic stroke patients: a retrospective study.

Background: Cerebrovascular diseases of the brain are usually defined by transient ischemic attacks and strokes. However, they can also cause brain injuries without neurological events. Silent brain infarcts (SBI) and leukoaraiosis are symptoms of both vascular and neurological abnormalities. This study aims to investigate the association between SBI, leukoaraiosis, and middle-aged patients with ischemic stroke. Methods: A single-center retrospective study of 50 middle-aged, ischemic stroke patients were studied from November 2022 and May 2023. The patients were divided into two groups based on the presence or absence of leukoaraiosis. History taking, physical examination, brain CT scan, and MRI were all part of the diagnostic process. Metabolic syndrome (MetS) was also assessed through various factors. The statistical analysis included descriptive statistics, logistic regression analysis, and chi-square test. Results: Out of the cohort comprising 50 patients, characterized by a mean age of 52.26 years (SD 5.29), 32 were male, constituting 64% of the sample. Among these patients, 26 individuals exhibited leukoaraiosis, with 17 of them (65.4%) also presenting with SBI. Moreover, within this cohort, 22 patients were diagnosed with MetS, representing 84.6% of those affected. The Multivariate logistic regression analysis showed a strong and independent association between leukoaraiosis and SBI. Individuals with leukoaraiosis were nearly five times more likely to have SBI compared to those without leukoaraiosis. Conclusion: The study highlights leukoaraiosis as a significant risk factor for SBI, alongside MetS. Advanced imaging techniques have facilitated their detection, revealing a higher prevalence among stroke patients, particularly associated with age and hypertension. Further research is needed to fully understand their complex relationship and develop better management strategies for cerebrovascular diseases, ultimately improving patient outcomes.

Influence of Connector Design on Displacement and Micromotion in Tooth-Implant Fixed Partial Dentures Using Different Lengths and Diameters: A Three-Dimensional Finite Element Study.

The literature presents insufficient data evaluating the displacement and micromotion effects resulting from the combined use of tooth-implant connections in fixed partial dentures. Analyzing the biomechanical behavior of tooth-implant fixed partial denture (FPD) prothesis is vital for achieving an optimum design and successful clinical implementation. The objective of this study was to determine the relative significance of connector design on the displacement and micromotion of tooth-implant-supported fixed dental prostheses under occlusal vertical loading. A unilateral Kennedy class I mandibular model was created using a 3D reconstruction from CT scan data. Eight simulated designs of tooth-implant fixed partial dentures (FPDs) were split into two groups: Group A with rigid connectors and Group B with non-rigid connectors. The models were subjected to a uniform vertical load of 100 N. Displacement, strain, and stress were computed using finite element analysis. The materials were defined as isotropic, homogeneous, and exhibiting linear elastic properties. This study focused on assessing the maximum displacement in various components, including the bridge, mandible, dentin, cementum, periodontal ligament (PDL), and implant. Displacement values were predominantly higher in Group B (non-rigid) compared to Group A (rigid) in all measured components of the tooth-implant FPDs. Accordingly, a statistically significant difference was observed between the two groups at the FPD bridge (p value = 0.021 *), mandible (p value = 0.021 *), dentin (p value = 0.043 *), cementum (p value = 0.043 *), and PDL (p value = 0.043 *). Meanwhile, there was an insignificant increase in displacement values recorded in the distal implant (p value = 0.083). This study highlighted the importance of connector design in the overall stability and performance of the prosthesis. Notably, the 4.7 mm × 10 mm implant in Group B showed a displacement nearly 92 times higher than its rigid counterpart in Group A. Overall, the 5.7 mm × 10 mm combination of implant length and diameter showcased the best performance in both groups. The findings demonstrate that wider implants with a proportional length offer greater resistance to displacement forces. In addition, the use of rigid connection design provides superior biomechanical performance in tooth-implant fixed partial dentures and reduces the risk of micromotion with its associated complications such as ligament overstretching and implant overload, achieving predictable prognosis and enhancing the stability of the protheses.

Anterior Endocrowns as An Alternative to Core Crown restorations: A Systematic Review.

Restoring extensively damaged endodontically treated teeth presents a challenging task due to the state of biomechanical deterioration affecting long-term prognosis. Therefore, the study aims to assess and compare the biomechanical performance of endocrowns and post core-crown restorations in anterior endodontically treated teeth with severe coronal structure loss. Following PRISMA guidelines, a systematic search was conducted using PubMed, Scopus, Web of Science, and Google Scholar for articles published from January 2014 to March 2024. Two independent reviewers screened and selected studies based on the predefined inclusion and exclusion criteria. The included studies were analyzed using the QUIN tool for risk of bias assessment in in-vitro studies. Additionally, the biomechanical outcomes were collected for qualitative comparative analysis. Twelve studies were included in this systematic review. In most studies, Endocrowns demonstrated comparable fatigue resistance under load to failure to post core-crown restorations. Endocrowns without ferrule exhibited a higher rate of debonding but had significantly more repairable failures. Conversely, post core-crown restorations demonstrated higher fracture resistance with the presence of ferrule, but were associated with more catastrophic failure patterns. Additionally, endocrowns generated lower stress levels in both the restorative material and the luting material compared to post core-crown restorations. Among the tested materials, lithium disilicate ceramics provided the best biomechanical properties. Overall, the studies included provided sufficient information for most evaluation criteria of the QUIN risk of bias assessment tool. Endocrowns are a viable and conservative approach for restoring endodontically treated anterior teeth, offering comparable biomechanical performance to traditional post core-crown restorations and less catastrophic failures. The findings of this systematic review suggest that endocrown restorations, especially with lithium disilicate ceramics and proper ferrule design, can improve fracture resistance and longevity of rehabilitated teeth, enhancing patient outcomes for severely damaged anterior endodontically treated teeth.

Black sand nanoparticles and heat stress impacts the neurological and oxidative stress indices and splenic-renal histology of Clarias gariepinus.

In Egypt, while many studies have focused on the radiometry and mineralogy of black sands, research on their effects on nearby aquatic organisms is rare. This study aimed to assess the combined effects of heat stress (HS) and black sand nanoparticles (BS-NPs) on renal function, antioxidant responses (TAC, SOD, CAT), neuro-stress indicators (AchE, cortisol), and to conduct histopathological investigations in the kidney and spleen tissues of African catfish Clarias gariepinus over a 15-day period to exposure to control, HS (32 °C), BS (6.4 g/kg diet) and HS + BS groups. The outcomes revealed that thermal stress alone showed no significant difference from the control. However, creatinine and uric acid levels were significantly higher in the BS-NPs and HS + BS-NPs groups (p < 0.001). Antioxidant markers (TAC, SOD, and CAT) were substantially reduced across all treated groups (0.05 ≥ p < 0.0001). AchE levels were significantly elevated in BS-NPs and HS + BS-NPs (p < 0.001), while cortisol levels were higher in these groups but not significantly different in HS. Degeneration and necrosis in the white and red pulps, scattered lymphocytes, and increased collagen fiber surrounding blood vessels and the lining of the ellipsoid structure were all evident in the spleen, along with the enlargement of the melanomacrophage centers with big granular, irregular, and brown pigments (hemosiderin). Our study, therefore, provides new insights into how heat stress, an abiotic environmental factor, influences the toxicity of black sand nanoparticles in catfish.

Peficitinib halts acute kidney injury via JAK/STAT3 and growth factors immunomodulation.

Acute Kidney Injury (AKI) is characterized by a sudden loss of kidney function and its management continues to be a challenge. In this study the effect of peficitinib, a Janus kinase inhibitor (JAKi), was studied in an aim to stop the progression of AKI at an early point of injury. Adult male mice were injected with aristolochic acid (AA) a single dose (10 mg/kg, i.p) to induce AKI. Peficitinib was injected in one of the two tested doses (5 or 10 mg/kg, i.p) 1 h after AA injection and was continued daily for seven days. Histopathological evaluation showed that peficitinib alleviated necrosis and hyaline cast formation induced by aristolochic acid. It decreased serum creatinine and the kidney injury molecule-1 (KIM-1) elevated by AA. Peficitinib also mitigated AA induced oxidative stress through regulating total antioxidant capacity (TAC) and reduced glutathione (GSH) level in renal tissue. Additionally, renal sections isolated from groups that received peficitinib revealed a decrease in vascular endothelial growth factor receptor 1 interstitial expression and transforming growth factor-beta 1 (TGF-ß1) renal level. Peficitinib received groups showed a decrease in the active phosphorylated form of signal transducers and activators of transcription (STAT3). Moreover, peficitinib decreased renal protein levels and gene expression of the pro-inflammatory cytokines; interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ). These findings suggest that peficitinib is helpful in halting AKI progression into chronic kidney disease through modulating JAK/STAT3 dependent inflammatory pathways and growth factors involved in normal glomerular function.

Enhanced Antimicrobial Properties of Polymeric Denture Materials Modified with Zein-Coated Inorganic Nanoparticles.

Background: Polymeric denture materials can be susceptible to colonization by oral microorganisms. Zein-coated magnesium oxide nanoparticles (zMgO NPs) demonstrate antimicrobial activity. The aim of this study was to investigate the antimicrobial effect and adherence of different oral microorganisms on hybrid polymeric denture materials incorporated with zMgO NPs. Methods: Five types of polymeric denture materials were used. A total of 480 disc-shaped specimens were divided by material type (n=96/grp), then subdivided by zMgO NPs concentration: control with no nanoparticles and other groups with zMgO NPs concentrations of 0.3%, 0.5% and 1% by weight. Characterization of the polymeric denture materials incorporating zMgO NPs was done, and the antimicrobial activity of all groups was tested against four types of microorganisms: 1) Streptococcus mutans, 2) Staphylococcus aureus, 3) Enterococcus faecalis and 4) Candida albicans. The samples underwent an adherence test and an agar diffusion test. Experiments were done in triplicates. Results: The characterization of the hybrid samples revealed variation in the molecular composition, as well as a uniform distribution of the zMgO NPs in the polymeric denture materials. All hybrid polymeric denture materials groups induced a statistically significant antimicrobial activity, while the control groups showed the least antimicrobial activity. The agar diffusion test revealed no release of the zMgO NPs from the hybrid samples, indicating the NPs did not seep out of the matrix. Conclusion: The zMgO NPs were effective in reducing the adherence of the tested microorganisms and enhancing the antimicrobial activity of the polymeric denture materials. This antimicrobial effect with the polymeric dentures could aid in resisting microbial issues such as denture stomatitis.

Modulating the HSP90 control over NFκB/NLRP3/Caspase-1 axis is a new therapeutic target in the management of liver fibrosis: Insights into the role of TAS-116 (Pimitespib).

Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1ß, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-ß, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.

Bond strength and surface roughness assessment of novel antimicrobial polymeric coated dental cement.

Resin cement integrated with zein-incorporated magnesium oxide nanoparticles has previously been found to inhibit oral microbes and decrease bacterial biofilm. However, the bond strength and surface features of this biomaterial have yet to be investigated. The objective of this study was to evaluate the shear bond strength, mode of fracture, and surface roughness of resin cement modified with zein-incorporated magnesium oxide nanoparticles. Characterization of the cement was performed by X-ray diffraction, field emission scanning electron microscopy, and Fourier transform infrared spectroscopy. 126 human teeth were divided into 3 groups and cemented to lithium disilicate ceramic using resin cement with zein-incorporated magnesium oxide nanoparticles at concentrations of 0%, 1%, and 2% (n = 42). 21 samples of each group were subjected to the shear bond strength test, while the other 21 underwent thermocycling for 10,000 cycles before the test, after which all samples were evaluated for the mode of fracture. To assess surface roughness, resin cement disks were analyzed by a profilometer before and after undergoing thermocycling for 10,000 cycles. The shear bond strength of the cement with 1% and 2% nanoparticles was significantly higher than the control before thermocycling. The mode of fracture was found to be mainly adhesive with all groups, with the unmodified cement presenting the highest cohesive failure. There was no significant difference in surface roughness between the groups before or after thermocycling. The addition of zein-incorporated magnesium oxide nanoparticles to resin cement improved or maintained the shear bond strength and surface roughness of the resin cement.

Maximizing dental composite performance: Strength and hardness enhanced by innovative polymer-coated MgO nanoparticles.

INTRODUCTION: Zein-incorporated magnesium oxide nanoparticles (zMgO NPs) can influence the mechanical properties of dental materials. However, the effect of this addition on the mechanical properties of resin composite has yet to be investigated. The objective of this study was to add various concentrations of zMgO NPs to conventional, flowable, and bulk-fill composite and assess the effect on the compressive strength, flexural strength, and microhardness. METHODOLOGY: 150 samples each of conventional composite, flowable composite, and bulk-fill composite (n = 450) were enhanced with concentrations of zMgO NPs at 0 %, 0.3 %, 0.5 %, 1 %, and 2 % (n = 30). 10 samples of each group were randomly allotted to the compressive strength, flexural strength, or hardness test. Characterization of the specimens was performed by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. Two-way ANOVA test was used to compare between groups, and one-way ANOVA followed by Tukey's test was done at p = 0.05 to determine significance. RESULTS: Characterization yielded a uniform distribution of nanoparticles in the matrix and the formation of a new hybrid composite that maintained its properties. Composite of all types enhanced with 0.3 % and 0.5 % zMgO NPs demonstrated a statistically significant increase in compressive strength, flexural strength, and hardness when compared to the control (p < 0.05). The bulk-fill composite with zMgO NPs concentrations of all groups demonstrated a statistically significant increase (p < 0.05) in hardness when compared to the control. CONCLUSION: The modified composites' compressive strength, flexural strength, and hardness improved or remained consistent. CLINICAL SIGNIFICANCE: An improved dental resin composite will enhance the quality of care and patient experience. The augmented strength and hardness of resin composite is desirable in prolonging the durability of the restoration.

Hyaluronic acid impacts hematological endpoints and spleen histological features in African catfish (Clarias gariepinus).

Since its identification in the vitreous humour of the eye and laboratory biosynthesis, hyaluronic acid (HA) has been a vital component in several pharmaceutical, nutritional, medicinal, and cosmetic uses. However, little is known about its potential toxicological impacts on aquatic inhabitants. Herein, we investigated the hematological response of Clarias gariepinus to nominal doses of HA. To achieve this objective, 72 adult fish were randomly and evenly distributed into four groups: control, low-dose (0.5 mg/l HA), medium-dose (10 mg/l HA), and high-dose (100 mg/l HA) groups for two weeks each during both the exposure and recovery periods. The findings confirmed presence of anemia, neutrophilia, leucopoenia, lymphopenia, and eosinophilia at the end of exposure to HA. In addition, poikilocytosis and a variety of cytomorphological disturbances were observed. Dose-dependent histological alterations in spleen morphology were observed in the exposed groups. After HA removal from the aquarium for 2 weeks, the groups exposed to the two highest doses still exhibited a notable decline in red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin concentration, and an increase in mean corpuscular volume. Additionally, there was a significant rise in neutrophils, eosinophils, cell alterations, and nuclear abnormalities percentages, along with a decrease in monocytes, coupled with a dose-dependent decrease in lymphocytes. Furthermore, only the highest dose of HA in the recovered groups continued to cause a significant increase in white blood cells. White blood cells remained lower, and the proportion of apoptotic RBCs remained higher in the high-dose group. The persistence of most of the haematological and histological disorders even after recovery period indicates a failure of physiological compensatory mechanisms to overcome the HA-associated problems or insufficient duration of recovery. Thus, these findings encourage the inclusion of this new hazardous agent in the biomonitoring program and provide a specific pattern of hematological profile in HA-challenged fish. Further experiments are highly warranted to explore other toxicological hazards of HA using dose/time window protocols.

Transcriptome-Wide Association Study Reveals New Molecular Interactions Associated with Melanoma Pathogenesis.

A transcriptome-wide association study (TWAS) was conducted on genome-wide association study (GWAS) summary statistics of malignant melanoma of skin (UK Biobank dataset) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) gene expression weights to identify melanoma susceptibility genes. The GWAS included 2465 cases and 449,799 controls, while the gene expression testing was conducted on 103 cases. Afterward, a gene enrichment analysis was applied to identify significant TWAS associations. The melanoma's gene-microRNA (miRNA) regulatory network was constructed from the TWAS genes and their corresponding miRNAs. At last, a disease enrichment analysis was conducted on the corresponding miRNAs. The TWAS detected 27 genes associated with melanoma with p-values less than 0.05 (the top three genes are LOC389458 (RBAK), C16orf73 (MEIOB), and EIF3CL). After the joint/conditional test, one gene (AMIGO1) was dropped, resulting in 26 significant genes. The Gene Ontology (GO) biological process associated the extended gene set (76 genes) with protein K11-linked ubiquitination and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulate cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 that inhibit translation initiation in the host cell, cell cycle, translation factors, and DNA repair pathways full network. The gene-miRNA regulatory network identified 10 hotspot genes with the top three: TP53, BRCA1, and MDM2; and four hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was among the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions.

Mechanical Behaviour of Novel Nanohybrid Resin Composite Using Two Light Cure Systems.

INTRODUCTION: Zein-incorporated magnesium oxide nanoparticles (zMgO NPs) were found to be effective against the bacteria S. mutans, S. aureus, E. faecalis and C. albicans, and can impart this antimicrobial effect on the resin composite it is integrated with. However, the effect of different light curing systems on the mechanical properties of this novel biomaterial has yet to be investigated. The objective of this study was to assess the effect of light-emitting diode (LED) and quarts-tungsten halogen (QTH) light curing systems on the compressive strength, flexural strength, and microhardness of bulk-fill resin composite modified with zMgO NPs. METHODOLOGY: A Teflon mold was used to fabricate 180 bulk-fill composite samples with concentrations of zMgO NPs at 0%, 0.3% and 0.5% (n = 60). Samples of each group were allocated to light curing by LED or QTH, after which 10 samples of each group were allotted to a mechanical test. Characterization of the specimens was performed by X-ray diffraction, field emission scanning electron microscopy and Fourier transform infrared spectroscopy. Two-way ANOVA and Tukey's post-hoc test was conducted at P = .05 to determine significance. RESULTS: The characterization revealed a uniform distribution of nanoparticles in the matrix and the formation of a new hybrid composite that maintained its properties. The compressive strength of the 0.3% zMgO composite for the QTH group significantly increased, while the remaining groups underwent no significant change. There was no significant difference among the groups for the flexural strength and microhardness tests. CONCLUSION: The modified composites' compressive strength, flexural strength, and microhardness improved or remained consistent. Long-term clinical studies can further substantiate the enhanced resin composite. CLINICAL RELEVANCE: The modified composite will exhibit similar or improved mechanical properties whether an LED or QTH light cure device is used. The addition of an antimicrobial effect to bulk-fill resin composite will aid in the prevention of secondary caries.

A review of the neurobehavioural, physiological, and reproductive toxicity of microplastics in fishes.

Microplastics (MPs) have emerged as widespread environmental pollutants, causing significant threats to aquatic ecosystems and organisms. This review examines the toxic effects of MPs on fishes, with a focus on neurobehavioural, physiological, and reproductive impacts, as well as the underlying mechanisms of toxicity. Evidence indicates that MPs induce a range of neurobehavioural abnormalities in fishes, affecting social interactions and cognitive functions. Altered neurotransmitter levels are identified as a key mechanism driving behavioural alterations following MP exposure. Physiological abnormalities in fishes exposed to MPs are also reported, including neurotoxicity, immunotoxicity, and oxidative stress. These physiological disruptions can compromise the individual health of aquatic organisms. Furthermore, reproductive abnormalities linked to MP exposure are discussed, with a particular emphasis on disruptions in endocrine signaling pathways. These disruptions can impair reproductive success in fish species, impacting population numbers. Here we explore the critical role of endocrine disruptions in mediating reproductive effects after exposure to MPs, focusing primarily on the hypothalamic-pituitary-gonadal axis. Our review highlights the urgent need for interdisciplinary research efforts aimed at elucidating the full extent of MP toxicity and its implications for aquatic ecosystems. Lastly, we identify knowledge gaps for future research, including investigations into the transgenerational impacts, if any, of MP exposure and quantifying synergetic/antagonistic effects of MPs with other environmental pollutants. This expanded knowledge regarding the potential risks of MPs to aquatic wildlife is expected to aid policymakers in developing mitigation strategies to protect aquatic species.

Outcomes With Limus- vs Paclitaxel-Coated Balloons for Percutaneous Coronary Intervention: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Randomized controlled trials (RCTs) examining the outcomes with limus drug-coated balloons (DCBs) vs paclitaxel DCBs were small and underpowered for clinical endpoints. OBJECTIVES: This study sought to compare the angiographic and clinical outcomes with limus DCBs vs paclitaxel DCBs for percutaneous coronary intervention (PCI). METHODS: An electronic search of Medline, EMBASE, and Cochrane databases was performed through January 2024 for RCTs comparing limus DCBs vs paclitaxel DCBs for PCI. The primary endpoint was clinically driven target lesion revascularization (TLR). The secondary endpoints were late angiographic findings. Summary estimates were constructed using a random effects model. RESULTS: Six RCTs with 821 patients were included; 446 patients received a limus DCB, and 375 patients received a paclitaxel DCB. There was no difference between limus DCBs and paclitaxel DCBs in the incidence of TLR at a mean of 13.4 months (10.3% vs 7.8%; risk ratio [RR]: 1.32; 95% CI: 0.84-2.08). Subgroup analysis suggested no significant interaction among studies for de novo coronary lesions vs in-stent restenosis (Pinteraction = 0.58). There were no differences in the risk of major adverse cardiovascular events, cardiac mortality, or target vessel myocardial infarction between groups. However, limus DCBs were associated with a higher risk of binary restenosis (RR: 1.89; 95% CI: 1.14-3.12), late lumen loss (mean difference = 0.16; 95% CI: 0.03-0.28), and a smaller minimum lumen diameter (mean difference = -0.12; 95% CI: -0.22 to -0.02) at late follow-up. In addition, late lumen enlargement occurred more frequently (50% vs 27.5%; RR: 0.59; 95% CI: 0.45-0.77) with paclitaxel DCBs. CONCLUSIONS: Among patients undergoing DCB-only PCI, there were no differences in the risk of clinically driven TLR and other clinical outcomes between limus DCBs and paclitaxel DCBs. However, paclitaxel DCBs were associated with better late angiographic outcomes. These findings support the need for future trials to establish the role of new-generation limus DCBs for PCI.