Consensus Guideline on the Management of Epilepsy in Egypt: A National Delphi Consensus Study.

OBJECTIVE: In epilepsy, early diagnosis, accurate determination of epilepsy type, proper selection of antiseizure medication, and monitoring are all essential. However, despite recent therapeutic advances and conceptual reconsiderations in the classification and management of epilepsy, serious gaps are still encountered in day-to-day practice in Egypt as well as several other resource-limited countries. Premature mortality, poor quality of life, socio-economic burden, cognitive problems, poor treatment outcomes, and comorbidities are major challenges that require urgent actions to be implemented at all levels. In recognition of this, a group of Egyptian epilepsy experts met through a series of consecutive meetings to specify the main concepts concerning the diagnosis and management of epilepsy, with the ultimate goal of establishing a nationwide Egyptian consensus. METHODS: The consensus was developed through a modified Delphi methodology. A thorough review of the most recent relevant literature and international guidelines was performed to evaluate their applicability to the Egyptian situation. Afterward, several remote and live rounds were scheduled to reach a final agreement for all listed statements. RESULTS: Of 278 statements reviewed in the first round, 256 achieved ≥80% agreement. Live discussion and refinement of the 22 statements that did not reach consensus during the first round took place, followed by final live voting then consensus was achieved for all remaining statements. SIGNIFICANCE: With the implementation of these unified recommendations, we believe this will bring about substantial improvements in both the quality of care and treatment outcomes for persons with epilepsy in Egypt. PLAIN LANGUAGE SUMMARY: This work represents the efforts of a group of medical experts to reach an agreement on the best medical practice related to people with epilepsy based on previously published recommendations while taking into consideration applicable options in resource-limited countries. The publication of this document is expected to minimize many malpractice issues and pave the way for better healthcare services on both individual and governmental levels.

Multi-target rational design and synthesis of novel diphenyl-tethered pyrazolopyrimidines targeting EGFR and topoisomerase II with potential DNA intercalation and apoptosis induction.

Herein, we envisioned the design and synthesis of novel pyrazolopyrimidines (confirmed by elemental analysis, 1H and 13C NMR, and mass spectra) as multitarget-directed drug candidates acting as EGFR/TOPO II inhibitors, DNA intercalators, and apoptosis inducers. The target diphenyl-tethered pyrazolopyrimidines were synthesized starting from the reaction of phenyl hydrazine and ethoxymethylenemalononitrile to give aminopyrazole-carbonitrile 2. The latter hydrolysis with NaOH and subsequent reaction with 4-chlorobenzaldhyde afforded the corresponding pyrazolo[3,4-d]pyrimidin-4-ol 4. Chlorination of 4 with POCl3 and sequential reaction with different amines afforded the target compounds in good yields (up to 73 %). The growth inhibition % of the new derivatives (6a-m) was investigated against different cancer and normal cells and the IC50 values of the most promising candidates were estimated for HNO97, MDA-MB-468, FaDu, and HeLa cancer cells. The frontier derivatives (6a, 6i, 6k, 6l, and 6m) were pursued for their EGFR inhibitory activity. Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib as a reference standard. On the other side, compounds (6a, 6i, 6k, 6l, and 6m) underwent topoisomerase II (TOPO II) inhibitory assay. In particular, compounds 6a and 6l exhibited IC50s of 17.89 and 19.39 µM, respectively, surpassing etoposide with IC50 of 20.82 µM. Besides, the DNA fragmentation images described the great potential of both candidates 6a and 6l in inducing DNA degradation at lower concentrations compared to etoposide and doxorubicin. Moreover, compound 6l, with the most promising EGFR/TOPO II inhibition and DNA intercalation, was selected for further investigation for its apoptosis induction ability by measuring caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 proteins. Additionally, molecular docking was used to explain the SAR results based on the differences in the molecular features of the investigated congeners and the target receptors' topology.

Design and synthesis of novel pyrazolopyrimidine candidates as promising EGFR-T790M inhibitors and apoptosis inducers.

Aim: Our objective was to design and synthesize a new range of pyrazolopyrimidines while maintaining the key pharmacophoric features of EGFR tyrosine kinase inhibitors. Materials & methods: Percentage inhibition in 14 human cancer cell lines and IC50 values were recorded. Compounds 6c, 7e and 7f were examined against both wild and mutant (T790M) EGFR subtypes. Apoptosis markers, cell cycle arrest, apoptosis assay and molecular docking were performed. Results: Compounds 6c, 7e and 7f demonstrated superior inhibitory potentials against wild and mutant (T790M) EGFR subtypes. A molecular docking study showed that compounds 6c and 7e had the best fit. Conclusion: The designed candidates demonstrated superior inhibitory potential as promising EGFR-T790M inhibitors that agrees with the proposed rationale.

Loading of zinc and iron in grains of different wheat genotypes in the calcareous and floodplain soils of Bangladesh.

Major malnutrition in Bangladesh is zinc (Zn) and iron (Fe) deficiency as most people commonly depend on cereals, chiefly rice and wheat. The main objectives are to enhance Zn and Fe concentrations through the use of selected varieties and the application of respective fertilizers. Field experiments were conducted at Bangladesh Agricultural University (BAU) farm, Mymensingh (AEZ 9, non-calcareous soil) and at Bangladesh Institute of Nuclear Agriculture (BINA) substation, Ishwardi (AEZ 11, calcareous soil) for two consecutive wheat seasons (2014-15 and 2015-16) with 10 varieties and 15 advanced lines. Varieties BARI Gom 25, 27, 28 & 29 and breeding lines Vijay, HPYT-5, 15 & 21 and BL-1883 have been recognized as Zn-enriched wheat varieties (24-30 µg g-1). Among the genotypes, Zn further increased by 4-8 µg g-1 due to Zn fertilization. Concerning Fe-enriched wheat genotypes (24-30 µg g-1), five varieties viz. Shatabdi, Prodip, BARI Gom 25 & 28 and Sufi, and four lines such as HPYT-12, BL-1883, BL-1040 and Fery-60 have been identified. The grain Fe concentration of wheat genotypes increased when Fe was added, the increment being 6-12 µg g-1. A positive relationship between Zn and N is observed with increased protein content. The grain yield of wheat was increased by 3.8-25.7% due to Zn application over the varieties and locations but Fe addition had no effect. The result of the current study showed that a potential breeding line with appropriate fertilization can improve Zn and Fe levels in wheat grain, without incurring loss to wheat yield.

Vitamin D receptor gene polymorphism and its relation to cancer colon occurrence.

Cancer colon is the second most prevalent cancer for females and the third for males. Vitamin D's cellular impacts are achieved by 1,25 (OH) 2D binding to the Vitamin D receptor (VDR). This study aimed at assessing the relation between vitamin D receptor gene polymorphism and cancer colon. This case-control study included 50 colorectal cancer (CRC) cases which were candidates for colonoscopy and 50 controls with normal colonoscopy. The study was conducted in Suez Canal University hospitals. All cases were diagnosed with colonoscopy and confirmed with histopathology. Blood samples from study subjects were used for detection of vitamin D receptor FokI polymorphism. We found that more than two thirds of patients were males. Around half of the cases were over 60 years old. Most of the study participants were overweight (26%), obese (53%), non-alcoholics (99%), and non-smokers (72%). However, about one third of the patients were diabetic (31%). Noticeably, none of these factors was significantly variant among CRC group and normal colonoscopy group (p < 0.05). The most common presentation among cases with colon cancer was constipation (80%). Of the 100 studied cases, 74% had left-sided colon cancer, with a 66% of them were resectable. The odds ratio of VDR polymorphism between the cases and control groups was high (3 with 95% CI (0.3-31)), however it did not reach statistical significance (p= 0.3). Most of the cases with VDR polymorphism had colon cancer (75%). In conclusion, based on our findings, there was no correlation between colorectal cancer and vitamin D receptor gene polymorphism.

Risk Assessment of Fluxametamide Resistance and Fitness Costs in Fall Armyworm (Spodoptera frugiperda).

The fall armyworm (FAW), Spodoptera frugiperda, is one of the most devastating invasive polyphagous pests, which has attracted recent global attention by developing resistance to various insecticidal active ingredients with independent mode of action. Fluxametamide, a newly commercialized isoxazoline insecticide, is exceptionally selective towards several lepidopteran pests. The present study aimed to evaluate resistance risk in FAW to fluxametamide and the fitness costs associated with fluxametamide resistance. A field-collected and genetically mixed population of FAW was artificially selected through continuous exposure to fluxametamide. After successive selection of 10 generations, there was no obvious increase in the LC50 (RF: 2.63-fold). The realized heritability (h2) of fluxametamide resistance was estimated as h2 = 0.084 using a quantitative genetic approach. Compared with the susceptible F0 strain, the Flux-SEL (F10) strain of FAW displayed no significant cross-resistance to broflanilide, chlorantraniliprole, fipronil, indoxacarb, lambda cyhalothrin, spinetoram, and tetraniliprole, except emamectin benzoate (RF: 2.08-fold). Increased activity of glutathione S-transferase (ratio 1.94) was observed in the Flux-SEL (F10) strain of FAW, while the cytochrome P450 and carboxylesterase activities were not altered. The fluxametamide-selection significantly affected the development and reproductive traits of FAW with a lower R0, T and relative fitness (Rf = 0.353). The results alluded that the risk of fluxametamide resistance evolution in FAW is relatively lower; however, proactive implementation of resistance management approaches should be done to maintain the field efficacy of fluxametamide against FAW.

Biofortification of mungbean (Vigna radiata L. (Wilczek)) with boron, zinc and iron alters its grain yield and nutrition.

Mungbean [Vigna radiata L. (Wilczek)] is considered as an extremely nutritious crop possessing a high level of micronutrients, but their low bioavailability in the crop leads to micronutrient malnutrition in humans. Therefore, the present study was conducted to investigate the potential of nutrients viz. boron (B), zinc (Zn) and iron (Fe) biofortification on productivity, nutrient concentration and uptake as well as the economics of mungbean cultivation. In the experiment, the various combinations of RDF with ZnSO4.7H2O (0.5%), FeSO4.7H2O (0.5%) and borax (0.1%) were applied to mungbean variety ML 2056. The combined foliar application of Zn, Fe and B was highly efficient in increasing the yield of grain as well as straw in mungbean exhibiting maximum values i.e. 944 kg ha-1 and 6133 kg ha-1, respectively. Similar results for B, Zn and Fe concentration in grain (27.3 mg kg-1, 35.7 mg kg-1 and 187.1 mg kg-1, respectively) and straw (21.1 mg kg-1, 18.6 mg kg-1 and 376.1 mg kg-1, respectively) of mungbean were observed. Also, uptake of Zn and Fe by grain (31.3 g ha-1 and 164.4 g ha-1, respectively), as well as straw (113.7 g ha-1 and 2295.0 g ha-1, respectively), was maximum for the above treatment. Whereas, the B uptake was found to enhance significantly through the combined application of B, Zn and Fe, where the values 24.0 g ha-1 and 128.7 g ha-1 corresponded to grain and straw, respectively. Thus, combined use of ZnSO4.7H2O (0.5%) + FeSO4.7H2O (0.5%) and borax (0.1%) significantly improved the yield outcomes, the concentration of B, Zn and Fe, uptake and economic returns of mungbean cultivation to alleviate the B, Zn and Fe deficiency.

The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain.

Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.

New [1,2,4]triazolo[4,3-c]quinazolines as intercalative Topo II inhibitors: Design, synthesis, biological evaluation, and in silico studies.

Fifteen quinazoline derivatives were designed and synthesized as DNA intercalators. The cytotoxicity of the designed members was assessed against HCT-116 and HepG2 cancer cell lines. In addition, the topoisomerase II (Topo II) inhibitory effect was assessed. Compound 16 was the most cytotoxic and Topo II inhibitor with low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 showed Topo II catalytic inhibitory effect at a concentration of 10 µM. Further mechanistic investigations revealed the capability of compound 16 to induce apoptosis in HCT-116 cells and arrest the growth at the S and G2/M phases. Also, compound 16 showed a significant increase in the level of BAX (2.18-fold) and a marked decrease in the level of Bcl-2 (1.9-fold) compared to the control cells. In silico studies revealed the ability of the synthesized members to bind to the DNA-Topo II complex.

Silver nanoparticles induced testicular damage targeting NQO1 and APE1 dysregulation, apoptosis via Bax/Bcl-2 pathway, fibrosis via TGF-ß/α-SMA upregulation in rats.

In medicine, silver nanoparticles (AgNPs) are employed often. They do, however, have negative impacts, particularly on the reproductive organs. This research aimed to assess AgNP impact on the testis and the possible intracellular mechanisms to induce testicular deteriorations in rats at various concentrations and different time intervals. Sprague Dawley rats (n = 40) were allocated into four equal groups: the control one, and three other groups injected intra-peritoneally with AgNP solution 0.25, 0.5, and 1 mg/kg b.w. respectively for 15 and 30 days. Our findings revealed that AgNPs reduced body and testicular weights, estradiol (E2) and testosterone (T) hormone levels, and sperm parameters while elevating the nitric oxide and malondialdehyde levels with inhibition of reduced glutathione contents in testicular tissue. Interestingly, AgNPs significantly upregulated the testicular inducible nitric oxide synthase, B cell lymphoma 2 (Bcl-2)-associated X, transforming growth factor, and alpha-smooth muscle actin (α-SMA) expression levels. However, apurinic/apyrimidinic endo deoxyribonuclease 1 (APE1), NAD (P) H quinone dehydrogenase 1 (NQO1), and Bcl-2 expression levels were all downregulated indicating exhaustion of body antioxidant and repairing defense mechanisms in testicles in comparison with the control rats. Various histological alterations were also detected which dramatically increased in rats sacrificed after 30 days such as loss of the lining cells of seminiferous tubules with no spermatozoa and tubular irregularities associated with thickening of their basement membranes. Immunolabeling implicated in the apoptotic pathway revealed a negative expression of Bcl-2 and marked immunoreactivity for caspase-3 after 30 days of AgNP treatment in comparison to the control rats. To our knowledge, there have been no previous publications on the role of the α-SMA, APE1, and NQO1 genes in the molecular pathogenesis of AgNP testicular cytotoxicity following AgNP acute and chronic exposure.

Selection of Lentil (Lens Culinaris (Medik.)) Genotypes Suitable for High-Temperature Conditions Based on Stress Tolerance Indices and Principal Component Analysis.

Legumes, including lentil, are a valuable source of carbohydrates, fiber, protein and vitamins and minerals. Their nutritional characteristics have been associated with a reduction in the incidence of various cancers, HDL cholesterol, type 2 diabetes and heart disease. Among these quality parameters, lectins have been associated with reducing certain forms of cancer, activating innate defense mechanisms and managing obesity. Protease inhibitors such as trypsin and chymotrypsin inhibitors have been demonstrated to reduce the incidence of certain cancers and demonstrate potent anti-inflammatory properties. Angiotensin I-converting enzyme (ACE) inhibitor has been associated with a reduction in hypertension. Therefore, legumes, including lentils, should be part of our daily food intake. However, high temperatures at the terminal stage is a major abiotic constraint leading to a reduction in lentil yield and seed quality. Thus, the selection of heat-tolerant genotypes is essential to identifying the potential for high yields with stable performance. To select lentil genotypes, an experiment was conducted with 60 genotypes including local landraces, advanced breeding lines, commercial varieties and exotic germplasm under stress and non-stress conditions from 2019 to 2020. This study was followed by a subset study involving screening based on a few physicochemical parameters and reproductive traits along with field performances. Different tolerance indices (i.e., stress susceptible index (SSI), relative heat index (RHI), tolerance (TOL), mean productivity (MP), stress tolerance index (STI), geometric mean productivity (GMP), yield index (YI), yield stability index (YSI), heat-resistance index (HRI), modified stress-tolerance index (MSTI), abiotic tolerance index (ATI) and stress susceptibility percentage (SSPI)) were used for the selection of the genotypes along with field performance. Biplot analysis was further performed for choosing the most suitable indices. Based on principal components analysis, the GMP, MP, RRI, STI, YI, YSI, ATI and MSTI indices were identified as the most reliable stress indicators, and these indicators might be used for distinguishing heat-tolerant genotypes. Based on the stress indices, the genotypes BLX 05002-3, BLX 10002-20, LRIL-21-1-1-1-1, LRIL-21-1-1-1-1-6 and BLX 09015 were selected as the most stable and heat-tolerant genotypes. In contrast, the genotypes LG 198, Bagura Local, BLX 0200-08-4, RL-12-178, Maitree, 91517 and BLX 11014-8 were selected as the most heat sensitive. Data also exhibited an average yield reduction of 59% due to heat stress on the lentils. Moreover, eight heat-tolerant (HT) genotypes (BLX 09015, PRECOZ, LRL-21-112-1-1-1-1-6, BLX 05002-3, LR-9-25, BLX 05002-6, BARI Masur-8 and RL-12-181), and two heat-susceptible (HS) genotypes (BLX 12009-6, and LG 198) were selected from the screened genotypes and subjected to further analysis by growing them in the following year under similar conditions to investigate the mechanisms associated with heat tolerance. Comparative studies on reproductive function and physiochemical traits revealed significantly higher pollen viability, proline accumulation, relative water content, chlorophyll concentration and a lower membrane stability index in HT genotypes under heat stress. Therefore, these heat-tolerant genotypes could be used as the parents in the hybridization program for achieving heat-tolerant transgressive segregation.

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

Biofortification of oil quality, yield, and nutrient uptake in Indian mustard (Brassica juncea L.) by foliar application of boron and nitrogen.

Indian mustard (Brassica juncea L.) is an essential oilseed crop that offers important nutrients to human beings. However, the concurrent micronutrient deficiencies including boron (B), sulfur (S), and nitrogen (N) could pose a significant threat to public health. Therefore, this study was conducted at the Punjab Agricultural University, Ludhiana, with nine treatments, i.e., T1-Control (recommended NPK only), T2- borax (0.5%) at flowering, T3-borax (1.0%) at flowering,T4- borax (0.5%) + urea (1.0%) at flowering,T5-borax (1.0%) + urea (1.0%) at flowering, T6-borax (0.5%) at flowering + capsule formation, T7-borax (1.0%) at flowering + capsule formation, T8-borax (0.5%) + urea (1.0%) at flowering + capsule formation, T9-borax (1.0%) + urea (1.0%) at flowering + Capsule formation, replicated three times in a randomized block design for 2 years (2020-2021 and 2021-2022). The foliar application of borax (1.0%) + urea (1.0%) at the flowering and capsule formation stage (treatment T9) was highly efficient in increasing food quality parameters such as crude fiber, total soluble solids (TSS), and protein content with maximum values of 3.77, 24.9, and 27.53%, respectively. Also, maximum yields of seed as well as stover for treatment T9 were 1.376 and 6.625 kg ha-1, respectively. Similarly, the results for B, S, and N concentrations in seed (27.71 mg kg-1, 17.69 mg kg-1, and 2.35%), as well as stover (25.92 mg kg-1, 17.31 mg kg-1, and 0.33%), were maximum in treatment T9. Also, B, S, and N uptake by seed (38.18 g ha-1, 24.40 g ha-1, and 32.05 Kg ha-1) and stover (172.55 g ha-1, 115.44 g ha-1, and 21.99 Kg ha-1) were maximum for the treatment T9 involving borax (1.0%) + urea (1.0%) at the flowering and capsule formation stage. Whereas, the concentration and uptake decreased in the treatments involving the sole application of borax and urea. Therefore, the application of borax (1.0%) and urea (1.0%) at the flowering and capsule formation stage significantly improved the quality parameters, seed and stover yield, nutrient concentration, and uptake over control and could be used to alleviate the B, S, and N deficiency in Indian mustard.

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M.

New 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFRWT). Compound 12b was the most potent member showing an IC50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFRT790M) (IC50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFRWT and EGFRT790M.

Interactive Effects of Molybdenum, Zinc and Iron on the Grain Yield, Quality, and Nodulation of Cowpea (Vignaunguiculata (L.) Walp.) in North-Western India.

Micronutrient deficiency is a major constraint for the growth, yield and nutritional quality of cowpea which results in nutritional disorders in humans. Micronutrients including molybdenum (Mo), iron (Fe) and zinc (Zn) play a pivotal role in crop nutrition, and their role in different metabolic processes in crops has been highlighted. In order to increase the nutritional quality of cowpea, a field experiment was conducted for two years in which the effect of Mo along with iron (Fe) and zinc (Zn) on productivity, nitrogen and micronutrient uptake, root length and the number of nodules in cowpea cultivation was investigated. It was found that the foliar application of Fe and Zn and their interaction with Mo application through seed priming as well as soil application displayed increased yield, nutrient concentration, uptake and growth parameters which helped to enhance the nutritional quality of cowpea for consumption by the human population. The results of the above experiments revealed that among all the treatments, the soil application of Mo combined with the foliar application of 0.5% each of FeSO4·7H2O and ZnSO4·7H2O (M2F3 treatment) enhanced the grain and stover yield of cowpea, exhibiting maximum values of 1402 and 6104.7 kg ha-1, respectively. Again, the M2F3 treatment resulted in higher Zn, Fe and Mo concentrations in the grain (17.07, 109.3 and 30.26 mg kg-1, respectively) and stover (17.99, 132.7 and 31.22 mg kg-1, respectively) of cowpea. Uptake of Zn, Fe and Mo by the grain (25.23, 153.3 and 42.46 g ha-1, respectively) as well as the stover (104.2, 809.9 and 190.6 g ha-1, respectively) was found to be maximum for the M2F3 treatment. The root length (30.5 cm), number of nodules per plant (73.0) and N uptake in grain and stover (55.39 and 46.15 kg ha-1) were also higher for this treatment. Overall, soil application of Mo along with the foliar application of FeSO4·7H2O (0.5%) and ZnSO4·7H2O (0.5%) significantly improved yield outcomes, concentration, uptake, root length, nodules plant-1 and N uptake of cowpea to alleviate the micronutrient deficiency.

Characterization of Phytochemicals, Nutrients, and Antiradical Potential in Slim Amaranth.

Slim amaranth (A. hybridus) having a C4 photosynthetic pathway with diverse variability is a climate-resilient crop that tolerates abiotic stresses. Owing to the high productivity of the C4 pathway, we have been searching for suitable accessions as preferable high-yielding antioxidant-enriched cultivars with ample bioactive compounds, or for future breeding programs to improve bioactive compounds as a source of natural antioxidants. Twelve slim amaranth accessions were tested for nutraceuticals, phytopigments, radical scavenging capacity (two different assays), vitamins, total flavonoids, and total polyphenols content. Slim amaranth leaves contained ample dietary fiber, protein, moisture, and carbohydrates. The current investigation demonstrated that there was remarkable K, Ca, Mg (8.86, 26.12, and 29.31), Fe, Mn, Cu, Zn, (1192.22, 275.42, 26.13, and 1069.93), TP, TF (201.36 and 135.70), pigments, such as chlorophyll a, ab, and b, (26.28, 38.02, and 11.72), betalains, betaxanthins, betacyanins (78.90, 39.36, 39.53,), vitamin C (1293.65), ß-carotene, total carotenoids, (1242.25, 1641.07), and TA (DPPH, ABTS+) (27.58, 50.55) in slim amaranth leaves. The widespread variations were observed across the studied accessions. The slim amaranth accessions, AH11, AH10, and AH12, exhibited high profiles of antioxidants including high potentiality to quench radicals and can be selected as preferable high-yielding antioxidant-enriched cultivars with ample bioactive compounds. Phytopigments, flavonoids, vitamins, and phenolics of slim amaranth leaves showed intense activity of antioxidants. Slim amaranth could be a potential source of proximate phenolics, minerals, phytopigments, vitamins, and flavonoids for gaining adequate nutraceuticals, bioactive components, and potent antioxidants. Moderate yielding accessions having moderate phytochemicals can be used to develop new high-yielding antioxidant-enriched cultivars for future breeding programs to improve bioactive compounds as a source of natural antioxidants.

Silver nanoparticles induced hepatoxicity via the apoptotic/antiapoptotic pathway with activation of TGFß-1 and α-SMA triggered liver fibrosis in Sprague Dawley rats.

Despite the extraordinary use of silver nanoparticles (AgNPs) in medicinal purposes and the food industry, there is rising worry about potential hazards to human health and the environment. The existing study aims to assess the hepatotoxic effects of different dosages of AgNPs by evaluating hematobiochemical parameters, oxidative stress, liver morphological alterations, immunohistochemical staining, and gene expression to clarify the mechanism of AgNPs' hepatic toxic potential. Forty male Sprague Dawley rats were randomly assigned into control and three AgNPs intraperitoneally treated groups 0.25, 0.5, and 1 mg/kg b.w. daily for 15 and 30 days. AgNP exposure reduced body weight, caused haematological abnormalities, and enhanced hepatic oxidative and nitrosative stress with depletion of the hepatic GSH level. Serum hepatic injury biomarkers with pathological hepatic lesions where cholangiopathy emerges as the main hepatic alteration in a dosage- and duration-dependent manner were also elevated. Furthermore, immunohistochemical labelling of apoptotic markers demonstrated that Bcl-2 was significantly downregulated while caspase-3 was significantly upregulated. In conclusion, the hepatotoxic impact of AgNPs may be regulated by two mechanisms, implying the apoptotic/antiapoptotic pathway via raising BAX and inhibiting Bcl-2 expression levels in a dose-dependent manner. The TGF-ß1 and α-SMA pathway which triggered fibrosis with incorporation of iNOS which consequently activates the inflammatory process were also elevated. To our knowledge, there has been no prior report on the experimental administration of AgNPs in three different dosages for short and long durations in rats with the assessment of Bcl-2, BAX, iNOS, TGF-ß1, and α-SMA gene expressions.

Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View.

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.

Ameliorative impacts of chrysin against gibberellic acid-induced liver and kidney damage through the regulation of antioxidants, oxidative stress, inflammatory cytokines, and apoptosis biomarkers.

Gibberellic acid (GA3), a widely known plant growth regulator, has been mostly used in agriculture. Little is known regarding its toxicity or the impact of its metabolic mechanism on human health. The current study examined the protective impact of chrysin against GA3-induced liver and kidney dysfunctions at biochemical, molecular, and histopathological levels. Forty male albino rats were allocated into 4 groups. The control group received saline; the chrysin group received 50 mg/kg/BW orally daily for 4 weeks; the GA3 group received 55 mg/kg/BW GA3 via daily oral gavage for 4 weeks, and the protective group (chrysin + GA3) was administered both chrysin and GA3 at the same dosage given in chrysin and GA3 groups. Chrysin was administered 1 h earlier than GA3. The GA3 induced liver and kidney injuries as proven by the elevation of hepatic and renal markers with a significant increase in malondialdehyde levels. Furthermore, a decrease of catalase and glutathione was reported in the GA3-administered rats. Pre-administration of chrysin significantly protected the hepatorenal tissue against the deleterious effects of GA3. Chrysin restored the hepatorenal functions and their antioxidant ability to normal levels. Moreover, chrysin modulated the hepatorenal toxic effects of GA3 at the molecular level via the upregulation of the antiapoptotic genes, interleukin-10 (IL-10), hemoxygenase-1, and nuclear factor erythroid 2-related factor 2 expressions; the downregulation of the kidney injury molecule-1 and caspase-3 mRNA expressions; and a decrease in IL-1ß and tumor necrosis factor-α secretions. Additionally, the pre-administration of chrysin effectively attenuated the GA3-induced hepatorenal histopathological changes by regulating the immunoexpression of cytochrome P450 2E1 (CYP2E1) and pregnane X receptor, resulting in normal values at the cellular level. In conclusion, chrysin attenuated GA3-induced oxidative hepatorenal injury by inhibiting free-radical production and cytokine expression as well as by modulating the antioxidant, apoptotic, and antiapoptotic activities. Chrysin is a potent hepatorenal protective agent to antagonize oxidative stress induced by GA3.

Gibberellic acid-induced hepatorenal dysfunction and oxidative stress: Mitigation by quercetin through modulation of antioxidant, anti-inflammatory, and antiapoptotic activities.

The plant growth regulator gibberellic acid (GA3) is widely used in agriculture in many countries. However, little is known about its danger to human health or its physiologic and biochemical pathways. Our study examined the effect of GA3 on liver and kidney function and the effect of quercetin on the hepatorenal toxicity induced by GA3 in four groups of male albino rats. For 4 weeks, the control group (CNT) received saline, the quercetin group (QR) received daily intraperitoneal injections of quercetin (50 mg/kg/BW) dissolved in saline, the gibberellic acid group (GA3) received GA3 (55 mg/kg/BW) via oral gavage, and the protective group (QR) was injected with quercetin and gavaged with GA3 in the same doses used in the QR and GA3 groups (50 mg/kg/BW +GA3 and 55 mg/kg/BW). GA3 induced liver and kidney injury, as shown by elevated serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and gamma-glutamyl transferase (GPT, GOT, and GGT) as well as increased levels of creatinine, urea, and uric acid. Hepatorenal toxicity was demonstrated by a significant increase in levels of serum and tissue malondialdehyde (MDA) and decreased antioxidant enzyme activity, such as catalase (CAT) and superoxide dismutase (SOD), accompanied by a subsequent decrease in glutathione peroxidase (GPx) levels in liver and kidney tissue of GA3-treated rats. Administration of quercetin (QR) significantly protected hepatorenal tissue against the toxic effect of GA3 through normalization of the hepatic and renal function markers. It also retrieved the antioxidant ability by modulating the hepatorenal toxic effect at the molecular level through upregulation of antiapoptotic genes and downregulation of transforming growth factor-ß1 (TFG-ß1), cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-κB). Impairment of liver and kidney function was confirmed by histologic and immunohistochemical analyses. Pretreatment with quercetin was effective at attenuating histopathologic changes in hepatic and renal tissues by regulating the immunoexpression of caspase-3 and Bcl-2 to return them to more normal values. PRACTICAL APPLICATIONS: The confirmed hepatorenal dysfunction caused by GA3 was ameliorated by quercetin administration. Moreover, quercetin demonstrated the potential to reverse hepatorenal dysfunction by regulating inflammatory and antioxidant properties, inhibiting the production of free radicals and inflammation-associated cytokines, and modulating antioxidants and antiapoptotic activity.