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Current research aimed to develop nanocubosomes co-loaded with dual anticancer drugs curcumin and temozolomide for effective colon cancer therapy. Drugs co-loaded nanocubosomal dispersion was prepared by modified emulsification method using glyceryl monooleate (GMO), pluronic F127 and bovine serum albumin (BSA) as a lipid phase, surfactant, and stabilizer, respectively. The resulting nanocubosomes were characterized by measuring hydrodynamic particle size, particle size distribution (PSD), drug loading capacity (DL), encapsulation efficiency (EE), colloidal stability and drug release profile. We also physiochemically characterized the nanocubosomes by transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and x-rays diffraction (XRD) for their morphology, polymer drug interaction and its nature, respectively. Further, the in-vitro cell-uptake, mechanism of cell-uptake, in-vitro anti-tumor efficacy and apoptosis level were evaluated using HCT-116 colon cancer cells. The prepared nanocubosomes exhibited a small hydrodynamic particle size (PS of 150 ± 10 nm in diameter) with nearly cubic shape and appropriate polydispersity index (PDI), enhanced drug loading capacity (LC of 6.82 ± 2.03% (Cur) and 9.65 ± 1.53% (TMZ), high entrapment efficiency (EE of 67.43 ± 2.16% (Cur) and 75.55 ± 3.25% (TMZ), pH-triggered drug release profile and higher colloidal stability in various physiological medium. Moreover, the nanocubosomes showed higher cellular uptake, in-vitro cytotoxicity and apoptosis compared to free drugs, curcumin and temozolomide, most likely because its small particle size. In addition, BSA-stabilized nanocubosomes were actively taken by aggressive colon cancer cells that over-expressed the albumin receptors and utilized BSA as nutrient source for their growth. In short, this study provides a new and simple strategy to improve the efficacy and simultaneously overawed the adaptive treatment tolerance in colon cancer.

Abstract Background Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. Methods Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The β-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected E max of 90% MPE and ED50 of 6.4 μg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and β-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and β-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not β-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, β-endorphin antiserum and specific μ-opioid receptor antagonist CTAP. Lastly, cinobufagin- and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/β-endorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. Conclusions Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent β-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/β-endorphin pathway in antinociception.

Bulleyaconitine A (BAA), a C19-diterpenoid alkaloid, has been prescribed as a nonnarcotic analgesic to treat chronic pain over four decades in China. The present study investigated its inhibition in morphine-induced withdrawal symptoms, conditioned place preference (CPP) and locomotor sensitization, and then explored the underlying mechanisms of actions. Multiple daily injections of morphine but not BAA up to 300 μg/kg/day into mice evoked naloxone-induced withdrawal symptoms (i.e., shakes, jumps, genital licks, fecal excretion and body weight loss), CPP expression, and locomotor sensitization. Single subcutaneous BAA injection (30–300 μg/kg) dose-dependently and completely attenuated morphine-induced withdrawal symptoms, with ED50 values of 74.4 and 105.8 μg/kg in shakes and body weight loss, respectively. Subcutaneous BAA (300 μg/kg) also totally alleviated morphine-induced CPP acquisition and expression and locomotor sensitization. Furthermore, subcutaneous BAA injection also specifically stimulated dynorphin A expression in microglia but not astrocytes or neurons in nucleus accumbens (NAc) and hippocampal, measured for gene and protein expression and double immunofluorescence staining. In addition, subcutaneous BAA-inhibited morphine-induced withdrawal symptoms and CPP expression were totally blocked by the microglial metabolic inhibitor minocycline, dynorphin A antiserum, or specific KOR antagonist GNTI, given intracerebroventricularly. These results, for the first time, illustrate that BAA attenuates morphine-induced withdrawal symptoms, CPP expression, and locomotor sensitization by stimulation of microglial dynorphin A expression in the brain, suggesting that BAA may be a potential candidate for treatment of opioids-induced physical dependence and addiction.

Background. Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes and molecular signaling underlie the sensitization of nociceptive pathways. We previously found that the activation of microglial glucagon-like peptide 1 receptor (GLP-1R) could potently relieve formalin-, bone cancer-, peripheral nerve injury-, and diabetes-induced pain hypersensitivity. So far, little is known about how the gene profile changes upon the activation of GLP-1R signaling in the pathophysiology of neuropathic pain. Methods. Spinal nerve ligation (SNL) was performed to induce neuropathic pain in rats. Mechanical allodynia was assessed using von Frey filaments. The expression of IL-10, β-endorphin, and μ-opioid receptor (MOR) was examined by real-time quantitative polymerase chain reaction (qPCR) and whole-cell recording. Measurements of cellular excitability of the substantia gelatinosa (SG) neurons by whole-cell recording were carried out. R packages of differential gene expression analysis based on the negative binomial distribution (DESeq2) and weighted correlation network analysis (WGCNA) were used to analyze differential gene expression and the correlated modules among GLP-1R clusters in neuropathic pain. Results. The GLP-1R agonist, exenatide, has an antiallodynic effect on neuropathic pain, which could be reversed by intrathecal injections of the microglial inhibitor minocycline. Furthermore, differential gene expression analysis (WGCNA) indicated that intrathecal injections of exenatide could reverse the abnormal expression of 591 genes in the spinal dorsal horn induced by nerve injury. WGCNA revealed 58 modules with a close relationship between the microglial GLP-1R pathway and features of nerve injuries, including pain, ligation, paw withdrawal latency (PWL), and anxiety. The brown module was identified as the highest correlated module, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that inflammatory responses were most correlated with PWL. To further unravel the changes of hyperalgesia-related neuronal electrophysiological activity mediated by microglia GLP-1 receptors, whole-cell recording identified that MOR agonism stimulated a robust outward current in the sham groups compared with the spinal nerve ligation (SNL) groups. This inhibitory effect on the SNL group was more sensitive than that of the sham group after bath application of β-endorphin. Conclusions. Our results further confirmed that the GLP-1R pathway is involved in alleviating pain hypersensitivity mediated by spinal microglia activation, and inflammatory responses were the most correlated pathway associated with PWL changes in response to exenatide treatment. We found that the identification of gene regulation in response to GLP-1R activation is an effective strategy for identifying new therapeutic targets for neuropathic pain. Investigation for the activation of spinal microglial GLP-1R which might ameliorate inflammatory responses through gene expression and structural changes is providing a potential biomarker in pain management.

Redox titration problems are considered difficult for students to learn due to their abstract nature, the myriad amount of representations, and the mathematical competency required to learn and solve. The goal of this research project is to examine challenges students face in learning about redox titration-related problems, approaches they use in learning about electrochemical titration problems, and reliance on algorithmic problem-solving instead of conceptual understanding in solving these problems. The research project took place at the City College of New York, which is an urban, minority serving, and public institution. The research instrument used in this research investigation is a survey comprised of Likert-type and open-ended questions. The number of research participants is n = 184. The data was collected and analyzed and histograms and figures were made based on the data analysis. A single factor ANOVA method was performed on the Likert-type questions which showed evidence against the null hypothesis and that shows a strong relationship between variables. The data indicate that the principal barrier to learning about redox titration related problems is that students' reliance on algorithmic problems solving, rote learning, and mathematical approaches. Students' dependence on rote learning and memorization in problem solving could be attributed to the lack of well-developed understanding of the concepts. The investigation shows that students focus on surface features in learning and this translates to hindrance of knowledge transfer.

Abstract Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines—fluticasone propionate (FP) and salmeterol xinafoate (SAL)—for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency– > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.

Abstract The exponential development of resistance to conventional chemical insecticides adds another important motive for the creation of novel insecticidal active agents. One of the keys to meeting this challenge is the exploration of novel classes of insecticidal molecules with different modes of action. Herein, a novel series of spiro pyrimidine derivatives was prepared using some green synthetic methodologies such as microwave irradiation, and sonication under ultrasound waves. Spiro pyrimidine aminonitrile 1 is a key starting material for the synthesis of targets 2–9 by reaction with different carbon electrophiles and nitrogen nucleophiles. The structures of all the newly synthesized compounds were approved using spectral data. The toxicological efficiency and biological impacts of the synthesized spiro pyrimidine derivatives were assessed against Culex pipiens L. larvae. The toxicity of synthesized compounds showed remarkable variations against the C. pipiens larvae. Where, 3, 4 and 2 were the most efficient compounds with LC50 values of 12.43, 16.29 and 21.73 µg/mL, respectively. While 1 was the least potent compound with an LC50 value of 95.18 µg/mL. As well, other compounds were arranged according to LC50 values as follows 5 > 7 > 6 > 9 > 8. In addition, 3 and 4 exhibited significant prolongation of the developmental duration and greatly inhibited adult emergence. Moreover, many morphological deformities were observed in all developmental stages. Furthermore, cytotoxicity of the most effective compounds was assessed against the normal human cells (WI-38) as non-target organisms, where compounds 2, 4 and 3 showed weak to non-toxic effects. The study of binding affinity and correlation between chemical structure and reactivity was carried out using molecular docking study and DFT calculations to investigate their mode of action. This study shed light on promising compounds with larvicidal activity and biological impacts on the C. pipiens life cycle.

Abstract Background and Aims Bowel preparation is considered as major obstacle before colonoscopy, and it is often reported as the most feared part of the procedure. The aim of this study is to determine the difference in efficacy between a split dose of PEG and the previous day regimen in cleaning the colon, using Boston bowel preparation scale. In addition, also to evaluate patient satisfaction regarding the modality of preparation. Methods The study included 200 hospitalized patients undergoing colonoscopy at Beirut hospitals between 2021 and 2023. One of the two regimens will be prescribed randomly to the patients before colonoscopy: 98 (49%) in Group A (patients treated with PEG preparation as a split dose for 2 days), and 102 (51%) in Group B (patients taking PEG preparation as a whole dose). Data was analyzed using SPSS version 25. Results Patients were distributed between 105 (52.5%) males and 95 (47.5%) females. The top two indications for colonoscopy were bleeding (34%), change in bowel habits (constipation/diarrhea) (32%). Patients experienced adverse events noting cramps (48.5%), stomach ache (32%), headache (31%), vomiting (53%), nausea (53%), sleep disturbance (27%), bloating (26.5%), and malaise (26%). A statistically significant difference (p = 0.040) was detected in sleep disturbance: 20.4% of patients in group A and 33.3% of patients in group B. The average satisfaction score was 3.02 ± 1.03 over 4 (Group A) and 3.04 ± 0.99 over 4 (Group B) (p = 0.896). The average BBPS was 8.07 ± 1.14 (Group A) and 8.28 ± 1.0 (Group B) (p = 0.162). Conclusion The two administrations were almost similar in term of satisfaction and BBPS. As multiple factors like age, sexe, comorbidities may contribute in altering how much a given drug is safe and efficace, more research is needed to choose the best 3regimen for each patient.

The scientific grasp of the distribution and dynamics of land use and land cover (LULC) changes in South America is still limited. This is especially true for the continent’s hyperarid, arid, semiarid, and dry subhumid zones, collectively known as drylands, which are under-represented ecosystems that are highly threatened by climate change and human activity. Maps of LULC in drylands are, thus, essential in order to investigate their vulnerability to both natural and anthropogenic impacts. This paper comprehensively reviewed existing mapping initiatives of South America’s drylands to discuss the main knowledge gaps, as well as central methodological trends and challenges, for advancing our understanding of LULC dynamics in these fragile ecosystems. Our review centered on five essential aspects of remote-sensing-based LULC mapping: scale, datasets, classification techniques, number of classes (legends), and validation protocols. The results indicated that the Landsat sensor dataset was the most frequently used, followed by AVHRR and MODIS, and no studies used recently available high-resolution satellite sensors. Machine learning algorithms emerged as a broadly employed methodology for land cover classification in South America. Still, such advancement in classification methods did not yet reflect in the upsurge of detailed mapping of dryland vegetation types and functional groups. Among the 23 mapping initiatives, the number of LULC classes in their respective legends varied from 6 to 39, with 1 to 14 classes representing drylands. Validation protocols included fieldwork and automatic processes with sampling strategies ranging from solely random to stratified approaches. Finally, we discussed the opportunities and challenges for advancing research on desertification, climate change, fire mapping, and the resilience of dryland populations. By and large, multi-level studies for dryland vegetation mapping are still lacking.

Invasive species are permanently modifying the distribution and diversity of native species worldwide. For nearly two decades, a hornet, Vespa velutina nigrithorax (Hymenoptera: Vespidae), has been spreading in Europe. Due to its marked invasiveness, this yellow-legged hornet is of great economic and ecological concern, mainly because of the damage it causes to insects in general and bees in particular. Current management methods are sparse and ineffective. Naturally produced by insects, semio-chemicals have been proposed as integrated management tools in this context, either for disruption or mass trapping, as an alternative tool to conventional non-selective traps. Here, we focused on the venom gland, which produces the alarm pheromone. In previous studies, individuals showed marked diversity in their chemical profiles. However, to successfully conduct targeted pheromone-based trapping, the hornet’s chemical ecology must be thoroughly characterized. Therefore, it was necessary to better understand the chemical composition of the alarm pheromone of not only workers but also other V. v. nigrithorax females. First, we evaluated the differences in venom gland profiles between the four types of females: queens, foundresses, pre-winter gynes, and workers. Next, we experimentally explored the venom gland profiles of V. velutina nigrithorax workers and pre-wintering gynes by in vivo and in vitro approaches. We found 13 new compounds in the venom gland, of which 9 were identified (chain lengths: C8 to C12). Two compounds were found exclusively in reproductive females. Profiles differed among pre-wintering gynes, foundresses, and queens but not between pre-wintering gynes and workers. This result indicates that the chemical signature of the female venom gland changes over the course of life history: from pre-wintering gynes to foundresses to queens.

هدفت الدراسة إلى تحليل أثر تمكين المرأة على توزيع لدخل في العراق بافتراض وجود علاقة تأثير مهمة بين تمكين المرأة (اقتصادياً وتعليمياً) وتوزيع الدخل فيه. ولقياس تأثير تمكين المرأة في العراق على توزيع الدخل فقد تم اجراء انحدار توزيع الدخل المتمثل بمعامل جيني على متغيرات تمكين المرأة. تم استخدام نموذج ARDL لتقدير تأثير تمكين المرأة على توزيع الدخل، وقد أخذت النماذج المقدرة بالاعتبار تأثير حصة الفرد من الناتج المحلي الاجمالي ومربع الناتج المحلي الاجمالي لبيان امكانية أن تكون العلاقة غير خطية بين التنمية الاقتصادية وتوزيع الدخل. كشفت النتائج أن للتمكين الاقتصادي والتعليمي للمرأة في العراق تأثير توزيعي مهم، فمع المزيد من التمكين يتراجع معامل جيني (أي يتحسن توزيع الدخل). أثبتت نتائج تأثير حصة الفرد من الناتج المحلي الإجمالي ومربعه وجود علاقة غير خطية بين التنمية الاقتصادية وطريقة توزيعه. هذه النتيجة متوافقة مع فرضية كوزنتس التي تؤكد ان التنمية الاقتصادية تؤدي إلى زيادة تفاوت توزيع الدخل في مراحلها الأولى، بينما يميل التفاوت للانخفاض في مراحله المتقدمة، وإن العلاقة تأخذ شكل مقلوب حرف (U).

Twelve spiro thiazolidinone compounds (A–L) were synthesized via either conventional thermal or ultrasonication techniques using Fe2O3 nanoparticles. The modification of the traditional procedure by using Fe2O3 nanoparticles led to enhancement of the yield of the desired candidates to 78–93% in approximately half reaction time compared with 58–79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P212121 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10–17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15–23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters. [ABSTRACT FROM AUTHOR]