Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia.

Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.

Impact of Self-Monitoring Blood Glucose on Glycaemic Control Among Insulin-Treated Patients With Diabetes Mellitus in Northeastern Tanzania: A Randomised Controlled Trial.

Introduction: Tracking of blood glucose levels by patients and care providers remains an integral component in the management of diabetes mellitus (DM). Evidence, primarily from high-income countries, has illustrated the effectiveness of self-monitoring of blood glucose (SMBG) in controlling DM. However, there is limited data on the feasibility and impact of SMBG among patients in the rural regions of sub-Saharan Africa. This study is aimed at assessing SMBG, its adherence, and associated factors on the effect of glycaemic control among insulin-treated patients with DM in northeastern Tanzania. Materials and Methods: This was a single-blinded, randomised clinical trial conducted from December 2022 to May 2023. The study included patients with DM who had already been on insulin treatment for at least 3 months. A total of 85 participants were recruited into the study and categorised into the intervention and control groups by a simple randomization method using numbered envelopes. The intervention group received glucose metres, test strips, logbooks, and extensive SMBG training. The control group received the usual care at the outpatient clinic. Each participant was followed for a period of 12 weeks, with glycated haemoglobin (HbA1c) and fasting blood glucose (FBG) being checked both at the beginning and at the end of the study follow-up. The primary and secondary outcomes were adherence to the SMBG schedule, barriers associated with the use of SMBG, and the ability to self-manage DM, logbook data recording, and change in HbA1c. The analysis included descriptive statistics, paired t-tests, and logistic regression. Results: Eighty participants were analysed: 39 in the intervention group and 41 in the control group. In the intervention group, 24 (61.5%) of patients displayed favourable adherence to SMBG, as evidenced by tests documented in the logbooks and glucometer readings. Education on SMBG was significantly associated with adherence. Structured SMBG improved glycaemic control with a HbA1c reduction of -1.01 (95% confidence interval (CI) -1.39, -0.63) in the intervention group within 3 months from baseline compared to controls of 0.18 (95% CI -0.07, 0.44) (p < 0.001). Conclusion: Structured SMBG positively impacted glycaemic control among insulin-treated patients with DM in the outpatient clinic. The results suggest that implementing a structured testing programme can lead to significant reductions in HbA1c and FBG levels. Trial Registration: Pan African Clinical Trials Registry identifier: PACTR202402642155729.

EPI-Trans: an effective transformer-based deep learning model for enhancer promoter interaction prediction.

BACKGROUND: Recognition of enhancer-promoter Interactions (EPIs) is crucial for human development. EPIs in the genome play a key role in regulating transcription. However, experimental approaches for classifying EPIs are too expensive in terms of effort, time, and resources. Therefore, more and more studies are being done on developing computational techniques, particularly using deep learning and other machine learning techniques, to address such problems. Unfortunately, the majority of current computational methods are based on convolutional neural networks, recurrent neural networks, or a combination of them, which don't take into consideration contextual details and the long-range interactions between the enhancer and promoter sequences. A new transformer-based model called EPI-Trans is presented in this study to overcome the aforementioned limitations. The multi-head attention mechanism in the transformer model automatically learns features that represent the long interrelationships between enhancer and promoter sequences. Furthermore, a generic model is created with transferability that can be utilized as a pre-trained model for various cell lines. Moreover, the parameters of the generic model are fine-tuned using a particular cell line dataset to improve performance. RESULTS: Based on the results obtained from six benchmark cell lines, the average AUROC for the specific, generic, and best models is 94.2%, 95%, and 95.7%, while the average AUPR is 80.5%, 66.1%, and 79.6% respectively. CONCLUSIONS: This study proposed a transformer-based deep learning model for EPI prediction. The comparative results on certain cell lines show that EPI-Trans outperforms other cutting-edge techniques and can provide superior performance on the challenge of recognizing EPI.

The Synergistic Effect of Lemongrass Essential Oil and Flometoquin, Flonicamid, and Sulfoxaflor on Bemisia tabaci (Genn.) (Hemiptera: Aleyrodidae): Insights into Toxicity, Biochemical Impact, and Molecular Docking.

The whitefly, Bemisia tabaci (Genn.), is one of the most dangerous polyphagous pests in the world. Eco-friendly compounds and new chemical insecticides have gained recognition for whitefly control. In this study, the toxicity and biochemical impact of flometoquin, flonicamid, and sulfoxaflor, alone or combined with lemongrass essential oil (EO), against B. tabaci was studied. In addition, a molecular docking study was conducted to assess the binding affinity of the tested compounds to AchE. Based on the LC values, the descending order of the toxicity of the tested compounds to B. tabaci adults was as follows: sulfoxaflor > flonicamid > flometoquin > lemongrass EO. The binary mixtures of each of the tested compounds with lemongrass EO exhibited synergism in all combinations, with observed mortalities ranging from 15.09 to 22.94% higher than expected for an additive effect. Sulfoxaflor and flonicamid, alone or in combination with lemongrass EO, significantly inhibited AchE activity while only flonicamid demonstrated a significant impact on α-esterase, and none of the tested compounds affected cytochrome P450 or GST. However, the specific activity of P450 was significantly inhibited by the lemongrass/sulfoxaflor mixture while α-esterase activity was significantly inhibited by the lemongrass/flometoquin mixture. Moreover, the lemongrass EO and all the tested insecticides exhibited significant binding affinity to AchE with energy scores ranging from -4.69 to -7.06 kcal/mol. The current findings provide a foundation for utilizing combinations of essential oils and insecticides in the integrated pest management (IPM) of B. tabaci.

Comparing the efficacy of concomitant treatment of resistance exercise and creatine monohydrate versus multiple individual therapies in age related sarcopenia.

Aging-related sarcopenia is a degenerative loss of strength and skeletal muscle mass that impairs quality of life. Evaluating NUDT3 gene and myogenin expression as new diagnostic tools in sarcopenia. Also, comparing the concomitant treatment of resistance exercise (EX) and creatine monohydrate (CrM) versus single therapy by EX, coenzyme Q10 (CoQ10), and CrM using aged rats. Sixty male rats were equally divided into groups. The control group, aging group, EX-treated group, the CoQ10 group were administered (500 mg/kg) of CoQ10, the CrM group supplied (0.3 mg/kg of CrM), and a group of CrM concomitant with resistance exercise. Serum lipid profiles, certain antioxidant markers, electromyography (EMG), nudix hydrolase 3 (NUDT3) expression, creatine kinase (CK), and sarcopenic index markers were measured after 12 weeks. The gastrocnemius muscle was stained with hematoxylin-eosin (H&E) and myogenin. The EX-CrM combination showed significant improvement in serum lipid profile, antioxidant markers, EMG, NUDT3 gene, myogenin expression, CK, and sarcopenic index markers from other groups. The NUDT3 gene and myogenin expression have proven efficient as diagnostic tools for sarcopenia. Concomitant treatment of CrM and EX is preferable to individual therapy because it reduces inflammation, improves the lipid serum profile, promotes muscle regeneration, and thus has the potential to improve sarcopenia.

Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Electrospun network based on polyacrylonitrile-polyphenyl/titanium oxide nanofibers for high-performance supercapacitor device.

Nanofibers and mat-like polyacrylonitrile-polyphenyl/titanium oxide (PAN-Pph./TiO2) with proper electrochemical properties were fabricated via a single-step electrospinning technique for supercapacitor application. Scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), thermogravimetry (TGA), fourier transform infrared (FTIR), X-ray diffraction (XRD) and energy dispersive X-ray (EDX) were conducted to characterize the morphological and chemical composition of all fabricated nanofibers. Furthermore, the electrochemical activity of the fabricated nanofibers for energy storage applications (supercapacitor) was probed by cyclic voltammetry (CV), charge-discharge (CD), and electrochemical impedance spectroscopy (EIS). The PAN-PPh./TiO2 nanofiber electrode revealed a proper specific capacitance of 484 F g-1 at a current density of 11.0 A g-1 compared with PAN (198 F g-1), and PAN-PPh. (352 F g-1) nanofibers using the charge-discharge technique. Furthermore, the PAN-PPh./TiO2 nanofiber electrode displayed a proper energy density of 16.8 Wh kg-1 at a power density (P) of 2749.1 Wkg-1. Moreover, the PAN-PPh./TiO2 nanofiber electrode has a low electrical resistance of 23.72 Ω, and outstanding cycling stability of 79.38% capacitance retention after 3000 cycles.

TLR4, IgA and EpCAM Expression in Colorectal Cancer and Their Possible Association with Microbiota as a Pathogenic Factor; An Immunohistochemical and Genetic Study.

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC) is thought to be related to immune response against gut microbiota. TLR4, IgA, and EpCAM have a role in intestinal local immune response and their altered expression related to both IBD and CRC. Lipopolysaccharide (LPS) is the main activator of TLR4. The objective of this study is to evaluate the possible role of intestinal microbiota in the pathogenesis of IBD and CRC through expression of TLR4, IgA and EpCAM. METHODS: One hundred five cases were divided into (Group 1/ Control: 10 sections of normal colonic mucosa, Group 2/CRC: 51 cases, Group 3/IBD: 44 cases). Immunohistochemistry for TLR4, IgA, and EpCAM was done. LPS was assessed in all groups. TLR4 gene and protein expression were assessed in colorectal cancer cell line by RT-PCR and immunocytochemistry. RESULTS: There was a significant correlation between TLR4 and tumor grade (P value 0.003 and 0.01 respectively). A significant correlation was found between IgA expression and T stage (P value 0.02) and between EpCAM expression and histologic type (P value 0.02). In comparison of CRC patients to controls; there was a statistically significant different expression of TLR4 positivity, IgA positivity and EpCAM (P value <0.001, 0.004, <0.001 respectively). Patients with CRC were compared to colitis patients and there was a statistically significant different expression of IgA positivity and EpCAM expression (P value <0.001). There was significant higher expression of TLR4 in CRC cell line than the fibroblast by both PCR and immunocytochemistry (P-value: 0.003 and 0.024 respectively). LPS level in CRC patients was significantly higher than the control and IBD groups (P values <0.001 and <0.001 respectively). CONCLUSION: TLR4, IgA, EpCAM expression in both CRC and IBD might be related to the pathogenic role of microbiota and could represent potential prevention modalities and therapeutic targets.

The Role of Sequentially Monitored Laboratory Values and Inflammatory Biomarkers in Assessing the Severity of COVID-19.

With the onset of the pandemic in 2020, COVID-19 pneumonia has become a common cause for hospitalization and is associated with high mortality rates. Inflammatory biomarkers play a crucial role in understanding and monitoring the progression of various diseases, including COVID-19. The objective of this study was to assess the significance of sequentially monitored standard laboratory tests, including complete blood cell count, D-dimer, fibrinogen, ferritin, albumin, C-reactive protein (CRP), as well as newly calculated inflammatory biomarkers in predicting the severity and prognosis of COVID-19 pneumonia. This single-center retrospective study included 194 patients hospitalized due to COVID-19 pneumonia. Patients were grouped based on the severity of their clinical symptoms, with 134 categorized as severe disease and 60 as mild-moderate disease. The patients' demographic data and laboratory values at hospital admission and on the third day of hospitalization were comparatively evaluated. In the severe illness group, there were more complaints about shortness of breath and a significant drop in the SPO2 value was observed at the time of application (p =0.005 and p<0.001, respectively). The overall mortality rate in all patients was 9% (18/194), and all deaths occurred within the severe disease group. All laboratory parameters, with the exception of platelet count and ferritin levels, were significantly associated and correlated with the severity of the disease during the hospitalization period. Among the biomarkers, there was no significant difference in neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) on the first day, a significant increase was observed on the third day of hospitalization in the severe disease group (p=0.050 vs. 0.003 and p=0.073 vs. 0.020, respectively). No significant difference was observed only in the PNR (platelet/neutrophil ratio) value among the inflammatory biomarkers (p=0.090 vs. p=0.354). In conclusion, the SPO2 level of COVID-19 patients at admission and the subsequent laboratory parameters examined show a significant relationship with the severity of the disease. In addition, simple inflammation biomarkers derived from laboratory values have shown a very significant relationship and correlation in the diagnosis and follow-up of the disease. In both admission and follow-up evaluation, a more significant association was observed with CRP-related biomarkers such as CRP/albumin ratio and CRP/lymphocyte ratio rather than NLR and PLR, which are widely used in the literature, in showing the severity of COVID-19. In patients with pneumonia, the laboratory assessment made on the third day of hospitalization reflects the severity of the disease more clearly than on the first day.

Ledipasvir/Sofosbuvir in Hepatitis C Virus-Infected Children With Hematological Malignancies: A Pharmacokinetic Study.

PURPOSE: Children with hematological malignancies and chronic hepatitis C virus (HCV) infection are at a higher risk for rapid progression of liver disease and malignancy relapse due to multiple hepatitis flares and chemotherapy interruption. They are therefore potential candidates for microelimination of HCV infection. This study aimed to assess the effect of acute lymphoblastic leukemia (ALL) on the pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF) and the SOF major metabolite GS-331007. METHODS: This was a 24-week, prospective, controlled, open-label, 2-arm PK study of patients receiving 45/200 mg once-daily LDV/SOF orally for 12 weeks. Eligible patients were HCV-RNA-positive, treatment-naive children aged 6 to <12 years and/or weighing 17 to <35 kg with genotype 4 chronic HCV infection without cirrhosis. The primary efficacy and safety end points were the achievement of sustained virologic response for all patients with absence of any adverse events leading to permanent discontinuation of the study drug. Steady-state noncompartmental analysis was performed to determine the PK parameters of SOF, GS-331007, and LDV as the primary PK outcome. Dose suitability was based on the 90% CI of exposure geometric mean ratio percentage within 50% to 200% compared with adults. FINDINGS: Ten HCV-infected children with ALL (chemotherapy treatment group) and 12 eligible children with no malignancy (control group) were enrolled and completed the study period. All 22 patients achieved the sustained virologic response with no adverse events leading to interruption or permanent discontinuation of the study drug. Compared with the control group, the ALL group patients had similar SOF, GS-331007, and LDV exposure. Compared with adults, the AUCτ of GS-331007 was lower and the AUCτ and Cmax,ss of SOF and the Cmax,ss of LDV were modestly higher in the ALL group (acceptance limit, 50%-200%). However, the observed efficacy and favorable safety profile made these changes not clinically significant. IMPLICATIONS: Weight-based dosing of LDV/SOF (45/200 mg) is highly effective and safe among genotype 4 HCV-infected children weighing 17 to <35 kg and diagnosed with ALL undergoing maintenance chemotherapy. The similarity in the drug exposure, efficacy, and safety clinical end points between patients with and without hematological malignancy support their therapeutic equivalence. Further studies with a larger sample size may be required to confirm the safety of LDV/SOF in patients with ALL and to recommend appropriate dosing in children with hematological malignancies, if needed. CLINICALTRIALS: gov identifier: NCT03903185.

Psychosocial and mental profile of children with sickle cell disease and their caregivers.

Sickle cell disease (SCD), a chronic debilitating disorder that may negatively affect health-related quality-of-life (HRQoL). In this observational, case-control study, we aim to assess the prevalence of impaired psychosocial profile and poor HRQoL among SCD patients and their caregivers as well as to determine the association of such impairment with parameters of disease severity. Sixty-five children and adolescents with SCD and 65 age- and sex-matched healthy controls and their caregivers were recruited. Demographic and clinical characteristics were collected, and a thorough clinical and psychiatric assessments and HR QoL were conducted. Recruited children and adolescents with SCD were 34 (52.3%) boys and 31 (47.7%) girls, and their mean age was 11.40 ± 3.55. Most of them (n = 44, 67.7%) had sickle HbSß+, and vaso-occlusive crises were the most common causes for hospital admission (n = 24, 36.9%). Children with SCD and their caregivers had depression and anxiety symptoms scores higher than reported in the control group. Children with SCD had significantly less self-esteem and less QoL scores with the least scores were in the communication domain. This adverse psychological profile was significantly negatively correlated with the age of the child, duration of illness, number and duration of hospitalizations, disease severity score, and occurrence of complications. We conclude that HRQoL of children suffering from SCD, and their caregivers are adversely affected necessitating implementation of interventions which focus on reducing depressive symptoms, enhancing self-esteem and QoL.

Assessment of methomyl-induced adrenal gland disruption in rat fetuses and pups: Potential protective effects of propolis supplementation.

The present study aimed to unravel the possible adverse effects of methomyl on the developing adrenal gland of rat fetuses and pups. Additionally, this study explored the potential improving effects of propolis against these possible hazards induced by methomyl exposure. To achieve that, pregnant rats were divided into four groups: control group, received 1 mL distilled water, propolis group, received 1 mL propolis at a dose of 300 mg/kg, methomyl group, received 1 mL methomyl at a dose of 2 mg/kg, and combined group, received 1 mL methomyl followed by 1 mL propolis, an hour later at the same previous doses. The results revealed that methomyl exposure, during pregnancy and lactation, induced many histological and ultrastructural changes, caused DNA damage and downregulated the expression of steroidogenic acute regulatory (StAR) and CYP11B2 genes in the adrenal glands of both rat fetuses and pups. Interestingly, propolis supplementation demonstrated a remarkable ability to mitigate these deleterious effects and restored the histology and ultrastructure architecture of the adrenal glands of both fetuses and pups, as well as decreased DNA damage and upregulated the expression of StAR and CYP11B2 genes in the adrenal gland of rat fetuses and pups. In conclusion, our study highlights the potential hazardous impact of methomyl exposure during pregnancy and lactation on the development of the adrenal gland in rat fetuses and pups, moreover, the study presents a new approach to alleviate these effects through propolis administration which could be used as a dietary supplement to mitigate the adverse effects of methomyl exposure.

Design of an electromagnetic metallic metamaterial absorber for terahertz applications.

Metamaterial absorbers have diverse applications in the terahertz range. In this paper, a metallic metamaterial absorber is designed to work as a narrowband, wideband, or ultrawideband according to application. A systematic method with minimal computational requirements for the design is developed. The method is efficient since the only information required is the operating frequency and required bandwidth. A condition for zero reflection which ensures matching with free space is derived. The proposed design method is used for the design of narrowband, wideband, and ultrawideband absorbers. For each case the design parameters are different. The narrow bandwidth is less than 5%, while the wide band lies between 5 and 20%, and the ultrawideband is larger than 20%. The dimensions of the designed structure and material properties (εr″) are different for each case. The designed absorber is wide-angle and polarization-independent. The sensitivity of the designed material due to changes of physical dimensions and permittivity is studied. To validate results, reflectivity and absorptivity are calculated using CST package. The dimensions obtained from the developed method are a bit modified using trial and error. The results from the developed method and CST are in excellent agreement.

Could serum HMGB1 levels be a predictor associated with psoriatic arthritis?

Background/aim: Psoriasis is a chronic autoimmune disease that predominantly affects the skin and musculoskeletal system. We hypothesized that HMGB1, an inflammatory nuclear protein, may play a role in the musculoskeletal involvement of psoriasis. Methods: Forty patients with psoriasis and 45 with psoriatic arthritis were involved in the study; the results were compared with 22 healthy controls. Serum HMGB1 levels were evaluated from peripheral blood samples. Results: Serum HMGB1 levels were found to be significantly higher in patients with psoriasis regardless of joint involvement (p < 0.001). Also, HMGB1 levels were correlated with the extent of psoriasis. Conclusion: Serum HMGB1 levels may contribute to the progression of psoriasis to psoriatic arthritis and correlate with the severity of skin involvement.

Psoriasis is an autoimmune skin disease that may also affect the joints. Factors leading to the progression of psoriasis to psoriatic arthritis are still a mystery despite an increasing number of animal studies and real-life data. HMGB1 is a nuclear protein that leads to an increase in molecules that increase inflammation (TNF-α, IL-1 and IL-6) in the body. Until now, there was no report about the relationship between psoriatic arthritis and serum HMGB1 levels. Our study aimed to find any difference in HMGB1 levels between healthy and psoriatic patients. Psoriatic arthritis patients had higher levels of serum HMGB1 than patients with psoriasis. Also, HMGB1 levels were correlated with the severity of skin involvement. Our results showed that serum HMGB1 may indicate a high risk for developing psoriasis that involves the joints. Therefore the HMGB1 level in psoriasis patients can potentially serve as a predictor associated with disease severity and the risk of developing psoriatic arthritis.

Antimicrobial and antiviral evaluation of compounds from Holoptelea integrifolia: in silico supported in vitro study.

Holoptelea integrifolia, also known as the Indian Elm Tree, has been used in Ayurvedic medicine for its medicinal properties. In this study, two biologically active metabolites, 5(6) dihydrostigmast 22en 3-O-ß-glucoside (DHS) and 1-O-eicosanoyl glycerol-2'-O-ß-galactouronic (EGG), were isolated for the first time from the n-butanol fraction of H. integrifolia using a chromatographic technique and identified by NMR, and HRESI-MS. The antiviral and multidrug-resistant activities of these metabolites were evaluated as well as the n-butanol fraction. The n-butanol fraction of H. integrifolia exhibited weak antiviral effects, but DHS and EGG demonstrated significant antiviral activity against herpes simplex type-1 (HSV-1) and Coxsackie (CoxB4) viruses. Both metabolites showed lower IC50 values than the standard antiviral drug acyclovir, indicating their potency in inhibiting viral replication. EGG showed potent antiviral activity with minimal cytotoxicity at the highest concentration tested, presenting a selectivity index (SI) of 18.18 and 15.58 against HSV-1 and CoxB4 viruses, respectively. A preliminary assessment of the antibacterial activity of the n-butanol fraction and metabolites revealed that DHS had the highest inhibitory potency against drug-resistant strains, including MRSA and Carbapenem-resistant Klebsiella pneumonia. It also exhibited significant inhibitions against Fluconazole-resistant Candida albicans and ESBL - Escherichia coli. DHS displayed the lowest minimum inhibitory concentration (MIC) values, indicating its superiority as an antibacterial agent compared to EGG and the n-butanol fraction. Molecular docking analysis confirmed the antiviral and antibacterial actions of DHS and EGG by demonstrating their strong binding.

Potential significance of podoplanin immunohistochemical expression in papillary thyroid carcinoma.

Podoplanin (PDPN) is a lymphatic endothelial marker expressed by a range of human malignancies in which it has been shown to contribute to tumor progression and metastasis. However, there is a lack of the studies, examining the function of PDPN in thyroid cancer. The current study was performed to explore the possible diagnostic value of PDPN expression in papillary thyroid cancer (PTC) and to evaluate the marker's potential for prediction of regional lymph node metastasis. Lymphatic vascular density (LVD) and the stromal/cancer-associated fibroblasts (CAFs), labeled by PDPN, were examined in PTC compared to the other thyroid lesions. The current study included 50 cases of PTC and 50 cases of non-PTC thyroid lesions. Immunohistochemical staining was performed using monoclonal PDPN antibodies. Podoplanin expression was scored as positive and negative. Podoplanin expression was found in 36% of PTC cases, but it was not found in benign, low risk (borderline), or malignant lesions other than PTC. Furthermore, lymph node metastasis was significantly correlated with PDPN expression, LVD and CAFs (p-values < 0.00001, < 0.001 and 0.0002 respectively). These findings support the diagnostic utility of PDPN expression in PTC and its predictive value for LN metastasis.

The ameliorating effects of mesenchymal stem cells compared to α-tocopherol on apoptosis and autophagy in streptozotocin-induced diabetic rats: Implication of PI3K/Akt signaling pathway and entero-insular axis.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered a novel regenerative therapy that holds much potential. This study aimed to examine and compare the ameliorative effects of BM-MSCs compared to α-tocopherol (α-Toc) on apoptosis, autophagy, and ß-cell function in a rat model of streptozotocin (STZ)-induced diabetes and further analyzed the implications and interrelations of the entero-insular axis, and type I phosphoinositide 3-kinase (PI3K)/Akt signaling. Forty adult male albino rats were categorized into four groups (n = 10, in each): control group, STZ-induced diabetic group (single i.p. injection of STZ 45 mg/kg), diabetic and treated with BM-MSCs injection, diabetic and treatment with α-Toc p.o. The serum glucose, insulin, nitric oxide (NO), and catalase (CAT) were measured. Histopathological examination of the pancreas, the expression levels of insulin, CD44, caspase-3, autophagy markers, P13K/Akt, and pancreas/duodenum homeobox protein 1, in pancreatic tissue, and glucose-dependent insulinotropic polypeptide (GIP) in the duodenum were detected by hematoxylin and eosin staining, immunofluorescence labeling, and by quantitative real-time polymerase chain reaction. The diabetic rats showed reduced insulin, hyperglycemia, nitrosative stress (NO, CAT), augmented apoptosis (caspase 3), impaired autophagy (p62/SQSTM1, LC3), downregulated PI3K/Akt pathway and increased GIP expression, and degeneration of pancreatic islets. Treatment with either BM-MSCs or α-Toc suppressed the nitrosative stress, reduced apoptosis, recovered autophagy, upregulated PI3K/Akt pathway, and subsequently increased insulin levels, decreased blood glucose, and downregulated GIP expression with partial restoration of pancreatic islets. Based on our findings, the cytoprotective effects of BM-MSCs and α-Toc in type 1-induced diabetes appeared to be related to repaired autophagy and recovered PI3K/Akt signaling. Moreover, we reported their novel effects on reversing intestinal GIP expression level. The effect of BM-MSCs was notably superior to that of α-Toc.

Deep Neural Decision Forest (DNDF): A Novel Approach for Enhancing Intrusion Detection Systems in Network Traffic Analysis.

Intrusion detection systems, also known as IDSs, are widely regarded as one of the most essential components of an organization's network security. This is because IDSs serve as the organization's first line of defense against several cyberattacks and are accountable for accurately detecting any possible network intrusions. Several implementations of IDSs accomplish the detection of potential threats throughout flow-based network traffic analysis. Traditional IDSs frequently struggle to provide accurate real-time intrusion detection while keeping up with the changing landscape of threat. Innovative methods used to improve IDSs' performance in network traffic analysis are urgently needed to overcome these drawbacks. In this study, we introduced a model called a deep neural decision forest (DNDF), which allows the enhancement of classification trees with the power of deep networks to learn data representations. We essentially utilized the CICIDS 2017 dataset for network traffic analysis and extended our experiments to evaluate the DNDF model's performance on two additional datasets: CICIDS 2018 and a custom network traffic dataset. Our findings showed that DNDF, a combination of deep neural networks and decision forests, outperformed reference approaches with a remarkable precision of 99.96% by using the CICIDS 2017 dataset while creating latent representations in deep layers. This success can be attributed to improved feature representation, model optimization, and resilience to noisy and unbalanced input data, emphasizing DNDF's capabilities in intrusion detection and network security solutions.

First Emergence of NDM-5 and OqxAB Efflux Pumps Among Multidrug-Resistant Klebsiella pneumoniae Isolated from Pediatric Patients in Assiut, Egypt.

Introduction: New Delhi metallo-ß-lactamase (NDM)-producing K. pneumoniae poses a high risk, especially among Egyptian pediatric patients who consume carbapenems antibiotics very widely and without adequate diagnostic sources. In addition, presence of efflux pump genes such as OqxAB increases resistance against many groups of antimicrobials which exacerbates the problem faced for human health. This study aimed to determine NDM variants among K. pneumoniae strains isolated from pediatric patients in Egypt, analyze the presence of OqxAB genes, and molecular characterization of blaNDM-5-positive K. pneumoniae. Methods: Fifty-six K. pneumoniae isolates were recovered from pediatric patients, and tested for carbapenemase by modified carbapenem inactivation methods (mCIM) test. Minimum inhibitory concentrations of meropenem and colistin were determined by meropenem E-test strips and broth microdilution, respectively. PCR was used for the detection of the resistant genes (ESBL gene (blaCTX-M), carbapenemase genes (blaNDM, blaKPC) colistin resistant (mcr1, mcr2)) and genes for efflux pump (oqxA and oqxB). BlaNDM was sequenced. The effect of efflux pump in NDM-5-producing isolates was assessed by measuring MIC of ciprofloxacin and meropenem before and after exposure to the carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The horizontal gene transfer ability of blaNDM-5 was determined using liquid mating assay and PCR-based replicon typing (PBRT) was done to determine the major plasmid incompatibility group. Results: Twenty-nine isolates were positive for blaNDM-1, nine isolates were positive for blaNDM-5, and 15 isolates were positive for blaKPC. There is a significant increase of meropenem MIC of NDM-5-positive isolates compared with NDM-1-positive isolates. In addition, 38 isolates were positive for CTX-M, and 15 isolates were positive for mcr1. Both OqxA and OqxB were detected in 26 isolates and 13 isolates were positive for OqxA while 11 isolates were positive for OqxB only. All NDM-5-producing isolates except one isolate could transfer their plasmids by conjugation to their corresponding transconjugants (E. coli J53). Plasmid replicon typing showed that FII was predominant in NDM-5-producing K. pneumoniae. Similar strains were found between the three isolates and similarity was also detected between the two isolates. Conclusion: The highly resistant K. pneumoniae producing blaNDM-5 type was firstly isolated from pediatric patients. The association of efflux pump genes such as OqxAB is involved in resistance to ciprofloxacin. This highlighted the severity risk of blaNDM-5-positive K. pneumonia as it could transfer blaNDM-5 to other bacteria and has more resistance against carbapenems. This underlines the importance of continuous monitoring of infection control guidelines, and the urgent need for a national antimicrobial stewardship plan in Egyptian hospitals.

Luteolin/ZnO nanoparticles attenuate neuroinflammation associated with diabetes via regulating MicroRNA-124 by targeting C/EBPA.

OBJECTIVE: The most prevalent brain-specific microRNA, MicroRNA-124, exhibits anti-inflammatory properties. Luteolin nano-formulation with Zn oxide in the form of L/ZnO NPs may boost anti-diabetic properties; however, its beneficial effect on miRNAs is yet unknown in diabetes. The effectiveness of L/ZnONPs supplements in preventing diabetic neurodegeneration by modulating inflammatory responses in a diabetic model was investigated. METHODS: A diabetic rat model was induced by a high-fat diet and streptozotocin (30 mg/kg I.P.). Plasma glucose, insulin, and HOMR-IR levels, as well as cytokines, lipid peroxidation, GSH/GSSG, and glucose transporter 1, were determined along with the tight junction proteins occludin (OCLN) and zona occludens 1 (ZO-1). Moreover, the expressions of brain CCAAT/enhancer-binding protein (C/EBPA mRNA), miR-124, glial fibrillary acidic protein (GFAP), and NF-kBp65 were measured alongside the histological investigation. RESULTS: The results revealed that L/ZnO NPs were able to diminish lipid peroxidation, increase the activity of antioxidant enzymes, and reduce inflammation under oxidative stress. Consequently, it was able to reduce hyperglycemia, elevate insulin levels, and improve insulin resistance. Besides, L/ZnO NPs upregulate miR-124, reduce C/EBPA mRNA, increase BCl-2, and inhibit apoptosis. The results indicate that diabetes raises BBB permeability via tight junction protein decline, which is restored following L/ZnO NPs treatment. Luteolin/ZnO NPs regulate miR-124 and microglia polarization by targeting C/EBPA and are expected to alleviate inflammatory injury via modulation of the redox-sensitive signal transduction pathways. Luteolin/ZnO NPs have a novel target for the protection of the BBB and the prevention of neurological complications in diabetes.