Mechanistic insights into carvedilol's potential protection against doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.

The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Utilizing combusted PET plastic waste and biogenic oils as efficient pour point depressants for crude oil.

The deposition of paraffin on pipelines during crude oil transit and low-temperature restart processes poses a significant challenge for the oil industry. Addressing this issue necessitates the exploration of innovative materials and methods. Pour point depressants (PPDs) emerge as crucial processing aids to modify paraffin crystallization and enhance crude oil flow. This study focuses on the combustion of polyethylene terephthalate (PET) waste, a prevalent plastic, in two distinct oils (castor and jatropha). The resulting black waxy substances (PET/Castor and PET/Jatropha) were introduced in varying weights (1000, 2000, and 3000 ppm) to crude oil. The PET/castor oil combination demonstrated a remarkable reduction in pour point from 18 to -21 °C at 3000 ppm concentration, significantly more effective than PET/jatropha blends. Substantial decreases in viscosity (up to 75%) and shear stress (up to 72%) were also observed for both blends, most prominently at lower temperatures near the pour point. The synergistic effect of PET and oils as nucleating agents that alter crystallization patterns and restrict crystal growth contributes to this enhanced low-temperature flow. This highlights the potential of PET plastic waste as an economical, abundant, and eco-friendly additive to develop high-performance PPDs for crude oil.

Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

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

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

Orexins in apoptosis: a dual regulatory role.

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles.

Liver fibrosis is a disease with a great global health and economic burden. Existing data highlights itraconazole (ITRCZ) as a potentially effective anti-fibrotic therapy. However, ITRCZ effect is hindered by several limitations, such as poor solubility and bioavailability. This study aimed to formulate and optimize chitosan nanoparticles (Cht NPs) loaded with ITRCZ as a new strategy for managing liver fibrosis. ITRCZ-Cht NPs were optimized utilizing a developed 22 full factorial design. The optimized formula (F3) underwent comprehensive in vitro and in vivo characterization. In vitro assessments revealed that F3 exhibited an entrapment efficiency of 89.65% ± 0.57%, a 169.6 ± 1.77 nm particle size, and a zeta potential of +15.93 ± 0.21 mV. Furthermore, in vitro release studies indicated that the release of ITRCZ from F3 adhered closely to the first-order model, demonstrating a significant enhancement (p-value < 0.05) in cumulative release compared to plain ITRCZ suspension. This formula increased primary hepatocyte survival and decreased LDH activity in vitro. The in vivo evaluation of F3 in a rat model of liver fibrosis revealed improved liver function and structure. ITRCZ-Cht NPs displayed potent antifibrotic effects as revealed by the downregulation of TGF-ß, PDGF-BB, and TIMP-1 as well as decreased hydroxyproline content and α-SMA immunoexpression. Anti-inflammatory potential was evident by reduced TNF-α and p65 nuclear translocation. These effects were likely ascribed to the modulation of Hedgehog components SMO, GLI1, and GLI2. These findings theorize ITRCZ-Cht NPs as a promising formulation for treating liver fibrosis. However, further investigations are deemed necessary.

Eco-friendly nano-enabled fertilizers derived from date industry waste for sustainable and controlled-release of P, K and Mg nutrients: sorption mechanisms, controlled-release performance and kinetics.

Development of nano-enabled fertilizers from green waste is one of the effective options to enhance global agricultural productions and minimize environmental pollution. In this study, novel, eco-friendly and cost-effective nano- enabled fertilizers (NEF) were synthesized using the planetary ball milling procedure. The NEF (nDPF1and nDPF2) were prepared by impregnation of nanostructured date palm pits (nDPP) with (KH2PO4 + MgO) at 1:1 and 3:1 (w/w) ratios respectively. The nDPP, nDPF1 and nDPF2 were extensively characterized. The produced nano-fertilizers enhanced soil water retention capacity with nDPF2 being the most effective. The water retention capacity of nDPF2 treated soil was 5.6 times higher than that of soil treated with conventional fertilizers. In addition, the nDPF2 exhibited superior sustained lower release rates of P, K and Mg nutrients for longer release periods in comparison with the conventional fertilizers. For instance, P cumulative release percentages from conventional fertilizers, nDPF1 and nDPF2 in soil reached 22.41%, 10.82 and 8.9% respectively within 384 h. Findings from FTIR and XPS analyses suggested that hydrogen bonding and ligand exchange were the main interaction mechanisms of PO4-K-Mg ions with nDPP surface. The released kinetics data of the NEF revealed that power function was the best suitable model to describe the kinetics of P, K and Mg release data from NEF in water and soil. Pot study ascertained that the nano-enabled fertilizers (nDPF1 and nDPF2) significantly promoted biomass production and nutrient uptake of maize plants as compared to commercial fertilizer treated plants. The present work demonstrated the potential of NEF to increase nutrients uptake efficiency, mitigate moisture retention problem in arid soils and reduce nutrients loss through leaching and safeguard the environment.

Genome-wide scanning to identify and validate single nucleotide polymorphism markers associated with drought tolerance in spring wheat seedlings.

Unlike other growth stages of wheat, very few studies on drought tolerance have been done at the seedling stage, and this is due to the complexity and sensitivity of this stage to drought stress resulting from climate change. As a result, the drought tolerance of wheat seedlings is poorly understood and very few genes associated with drought tolerance at this stage were identified. To address this challenge, a set of 172 spring wheat genotypes representing 20 different countries was evaluated under drought stress at the seedling stage. Drought stress was applied on all tested genotypes by water withholding for 13 days. Two types of traits, namely morphological and physiological traits were scored on the leaves of all tested genotypes. Genome-wide association study (GWAS) is one of the effective genetic analysis methods that was used to identify target single nucleotide polymorphism (SNP) markers and candidate genes for later use in marker-assisted selection. The tested plant materials were genotyped using 25k Infinium iSelect array (25K) (herein after it will be identified as 25K) (for 172 genotypes) and genotyping-by-sequencing (GBS) (for 103 genotypes), respectively. The results of genotyping revealed 21,093 25K and 11,362 GBS-SNPs, which were used to perform GWAS analysis for all scored traits. The results of GWAS revealed that 131 and 55 significant SNPs were controlling morphological and physiological traits, respectively. Moreover, a total of eight and seven SNP markers were found to be associated with more than one morphological and physiological trait under drought stress, respectively. Remarkably, 10 significant SNPs found in this study were previously reported for their association with drought tolerance in wheat. Out of the 10 validated SNP markers, four SNPs were associated with drought at the seedling stage, while the remaining six SNPs were associated with drought stress at the reproductive stage. Moreover, the results of gene enrichment revealed 18 and six pathways as highly significant biological and molecular pathways, respectively. The selection based on drought-tolerant alleles revealed 15 genotypes with the highest number of different drought-tolerant alleles. These genotypes can be used as candidate parents in future breeding programs to produce highly drought-tolerant genotypes with high genetic diversity. Our findings in this study provide novel markers and useful information on the genetic basis of drought tolerance at early growth stages.

Novel nano-fertilizers derived from drinking water industry waste for sustained release of macronutrients: performance, kinetics and sorption mechanisms.

Nanotechnology has emerged as a promising approach for the controlled release of nutrients, particularly phosphorus and potassium. These essential plant nutrients are often applied in excess, leading to environmental pollution and loss of efficiency in crop production. Innovative economic and highly efficient fertilizers are urgently needed to achieve the targeted crop production worldwide in the presence of limited land and water resources. Therefore, in this study, novel, eco-friendly, cost-effective and enhanced efficiency nano-enabled fertilizers, NEF (nWTF1and nWTF2) were synthesized by impregnation of nanostructured water treatment residuals (nWTR) with (KH2PO4 + MgO) at 1:1 and 3:1 (w/w) ratios respectively using a planetary ball mill. The nWTR, nWTF1 and nWTF2 were extensively characterized. The water retention behavior and the sustained release of nutrients from the fabricated nano-enabled fertilizers (nWTF1 and nWTF2) in distilled water and sandy soil were investigated and monitored over time. The water retention capacity of the soil treated with nWTF2 after 26 days was 9.3 times higher than that of soil treated with conventional fertilizer. In addition, the nWTF2 exhibited lower release rates of P, K and Mg nutrients for longer release periods in comparison with the conventional fertilizers. This is a significant advantage over traditional fertilizers, which release nutrients quickly and can lead to leaching and nutrient loss. The main interaction mechanisms of PO4-K-Mg ions with nWTR surface were suggested. The results of the kinetics study revealed that power function was the best suitable model to describe the kinetics of P, K and Mg release data from NEF in water and soil. The produced NEF were applied to Zea maize plants and compared to commercial chemical fertilizer control plants. The obtained results revealed that the nano-enabled fertilizers (nWTF1 and nWTF2) significantly promoted growth, and P content compared with the commercial chemical fertilizer treated plants. The present work demonstrated the power of nano enabled fertilizers as efficient and sustained release nano-fertilizers for sustainable agriculture and pollution free environment.

The role of matrix metalloproteinase-2 and miR-196a2 in bronchial asthma pathogenesis and diagnosis.

Background: Bronchial asthma is a persistent inflammatory respiratory condition that restricts the passage of air and causes hyperresponsiveness. Chronic asthma can be classified into three categories: mild, moderate, and severe. Remodeling took place as the extracellular matrix accumulated in the walls of the airways. Inflammation occurs as a result of the damage caused by matrix metalloproteinase-2 (MMP-2) to basement membrane type IV collagen. The severity of asthma may be associated with miR-196a2. The objective of our study was to investigate the underlying mechanisms and clinical relevance of miR-196a2 and MMP-2 serum levels in relation to the severity of asthma. Methods: This study recruited 85 controls and 95 asthmatics classified as mild, moderate, or severe. Expression of miR-196a2 was measured by quantitative reverse transcriptase PCR. Using the enzyme-linked immunosorbent assay (ELISA), MMP-2, IL-6, and total immunoglobulin E (IgE) levels in the serum of asthmatics of various grades were compared to a control group. MMP-2's diagnostic and prognostic potential was determined using ROC curve analysis. This study also measured blood Eosinophils and PFTs. We examined MMP-2's connections with IgE, blood Eosinophils, and PFTs. Results: The current investigation found that miR-196a2 expression was significantly higher in the control group than in asthmatic patients as a whole. The study found that severe asthmatics had higher MMP-2, IL-6, and IgE serum levels than healthy controls. We identified the MMP-2 serum concentration cutoff with great sensitivity and specificity. Significant relationships between MMP-2 serum level and miR-196a2 expression in the patient group with severe asthmatics were found. The MMP-2, IL-6, and IgE serum levels were considerably higher in mild, moderate, and severe asthmatics than controls. The miR-196a2 expression and MMP-2 serum concentration correlated positively with IgE and blood eosinophils % and negatively with all lung function tests in the asthmatic patient group.Conclusion: the study revealed that the elevated miR-196a2 expression and serum concentration of MMP-2, IL-6, and IgE associated with elevated blood eosinophils % is associated with pathophysiology and degree of asthma severity. The miR-196a2 expression and MMP-2 serum concentration have a promising diagnostic and prognostic ability in bronchial asthma.

Corrigendum: Unveiling the therapeutic potential of exogenous ß-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis.

[This corrects the article DOI: 10.3389/fphar.2023.1239025.].

Exogenous application of nano-silicon, potassium sulfate, or proline enhances physiological parameters, antioxidant enzyme activities, and agronomic traits of diverse rice genotypes under water deficit conditions.

Water deficit is a critical obstacle that devastatingly impacts rice production, particularly in arid regions under current climatic fluctuations. Accordingly, it is decisive to reinforce the drought tolerance of rice by employing sustainable approaches to enhance global food security. The present study aimed at exploring the effect of exogenous application using different biostimulants on physiological, morphological, and yield attributes of diverse rice genotypes under water deficit and well-watered conditions in 2-year field trial. Three diverse rice genotypes (IRAT-112, Giza-178, and IR-64) were evaluated under well-watered (14400 m3/ha in total for the entire season) and water deficit (9170 m3/ha) conditions and were exogenously sprayed by nano-silicon, potassium sulfate, or proline. The results showed that drought stress substantially decreased all studied photosynthetic pigments, growth traits, and yield attributes compared to well-watered conditions. In contrast, antioxidant enzyme activities and osmoprotectants were considerably increased compared with those under well-watered conditions. However, the foliar application of nano-silicon, potassium sulfate, and proline substantially mitigated the deleterious effects of drought stress and markedly enhanced photosynthetic pigments, antioxidant enzyme activities, growth parameters, and yield contributing traits compared to untreated stressed control. Among the assessed treatments, foliar spray with nano-silicon or proline was more effective in promoting drought tolerance. The exogenous application of proline improved chlorophyll a, chlorophyll b, and carotenoids by 21.4, 19.6 and 21.0% followed by nano-silicon treatment, which enhanced chlorophyll a, chlorophyll b, and carotenoids by 21.1, 17.6 and 9.5% compared to untreated control. Besides, the application of proline demonstrated a superior improvement in the content of proline by 52.5% compared with the untreated control. Moreover, nano-silicon exhibited the maximum enhancement of catalase and peroxidase activity compared to the other treatments. The positive impacts of applied exogenously nano-silicon or proline significantly increased panicle length, number of panicles/plant, number of grains/panicle, fertility percentage, 1000-grain weight, panicle weight, and grain yield, compared to untreated plants under water deficit conditions. In addition, the physiological and agronomic performance of evaluated rice genotypes significantly contrasted under drought conditions. The genotype Giza-178 displayed the best performance under water deficit conditions compared with the other genotypes. Consequently, the integration of applied exogenously nano-silicon or proline with tolerant rice genotype as Giza-178 is an efficient approach to ameliorating drought tolerance and achieving agricultural sustainability under water-scarce conditions in arid environments.

Effect of intermittent fasting on adriamycin-induced nephropathy: Possible underlying mechanisms.

PURPOSE: Intermittent fasting (IF) has been shown to induce a well-organized adaptive defense against stress inside the cells, which increases the production of anti-oxidant defenses, repair of DNA, biogenesis of mitochondria, and genes that combat inflammation. So, the goal of the current investigation was to identify the effects of IF on rats with adriamycin (ADR)-induced nephropathy and any potential underlying mechanisms. METHODS: Four groups of 40 mature Sprague-Dawley male rats were allocated as follow; control, fasting, ADR, and ADR plus fasting. After 8 weeks of ADR administration urine, blood samples and kidneys were taken for assessment of serum creatinine (Cr), BUN, urinary proteins, indicators of oxidative damage (malondialdehyde (MDA), reduced glutathione (GSH) and Catalase (CAT) levels), histopathological examinations, immunohistochemical examinations for caspase-3, Sirt1, aquaporin2 (AQP2) and real time PCR for antioxidant genes; Nrf2, HO-1 in kidney tissues. RESULTS: IF significantly improved serum creatinine, BUN and urinary protein excretion, oxidative stress (low MDA with high CAT and GSH), in addition to morphological damage to the renal tubules and glomeruli as well as caspase-3 production during apoptosis. Moreover, IF stimulates significantly the expression of Sirt1 and Nrf2/HO-1 and AQP2. CONCLUSION: AQP2, Sirt1, Nrf2/HO-1 signaling may be upregulated and activated by IF, which alleviates ADR nephropathy. Enhancing endogenous antioxidants, reducing apoptosis and tubulointerstitial damage, and maintaining the glomerular membrane's integrity are other goals.

Cervical Spinal Cord Stimulation for Failed Neck Surgery Syndrome.

PURPOSE OF REVIEW: Cervical spine pain with or without radicular symptoms is a common condition leading to high utilization of the healthcare system with over 10 million medical visits per year. Many patients undergo surgical interventions and unfortunately are still left with neck and upper extremity pain, sometimes referred to as "Failed Neck Surgery Syndrome." When these options fail, cervical spinal cord stimulation can be a useful tool to decrease pain and suffering as well as reduce prescription medication use. RECENT FINDINGS: Spinal cord stimulation is a well-established therapy for chronic back and leg pain and is becoming more popular for neck and upper extremity pain. Recent studies have explored cervical spinal cord stimulation with successful outcomes regarding improved pain scores, functional outcomes, and reduction of prescription medication use. Continued research into cervical spinal cord stimulation is essential for maximizing its therapeutic potential for patients with chronic neck and upper extremity pain. This review highlights the importance of cervical spinal cord stimulation as an option for patients with failed neck surgery syndrome.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

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

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

LC-HRMS Profiling and Cytotoxic Potential of Actinomycetes Associated with the Red Sea Soft Coral Sarcophyton glaucum: In vitro and In silico Studies.

In the current study, the actinomycetes associated with the red sea-derived soft coral Sarcophyton glaucum were investigated in terms of biological and chemical diversity. Four different media, M1, ISP2, Marine Agar (MA), and Actinomycete isolation agar (AIA) were used for the isolation of three strains of actinomycetes that were identified as Streptomyces sp. UR 25, Micromonospora sp. UR32 and Saccharomonospora sp. UR 19. LC-HRMS analysis was used to investigate the chemical diversity of the isolated actinobacteria. The LC-HRMS data were statistically processed using MetaboAnalyst 5.0 viz to differentiate the extract groups and determine the optimal growth culturing conditions. Multivariate data statistical analysis revealed that the Micromonospora sp. extract cultured on (MA) medium is the most distinctive extract in terms of chemical composition. While, the Streptomyces sp. UR 25 extracts are differ significantly from Micromonospora sp. UR32 and Saccharomonospora sp. UR 19. Biological investigation using in vitro cytotoxic assay for actinobacteria extracts revealed the prominent potentiality of the Streptomyces sp. UR 25 cultured on oligotrophic medium against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7) and human colon adenocarcinoma (CACO2) cell lines (IC50 =3.3, 4.2 and 6.8 µg/mL, respectively). SwissTarget Prediction speculated that among the identified compounds, 16-deethyl, indanomycin (8) could have reasonable affinity on HDM2 active site. In this respect, molecular docking study was performed for compound (8) to reveal a substantial affinity on HDM2 active site. In addition, molecular dynamics simulations were carried out at 200 ns for the most active compound (8) compared to the co-crystallized inhibitor DIZ giving deeper information regarding their thermodynamic and dynamic properties as well.

Looking for a Novel Vegan Protein Supplement from Faba Bean, Lupine, and Soybean: a Dietary and Industrial Standpoint.

Global population growth poses a threat to sustainable development. Meanwhile, the use of plant proteins as healthy and sustainable alternatives to animal proteins needs further research. Therefore, this investigation was designed to study the nutritive, structural, and thermal properties of isolated protein fractions from different legumes, i.e., faba bean (FPI), soybean (SPI), and lupine (LPI). As a prospective plant-based protein powder, an equal mixture (MPI) of the three prior legume samples was formulated to study its properties compared to each sole sample. The alkaline extraction and isoelectric precipitation (AE-IP) technique was used for protein isolation. Results showed that all protein isolates had reasonable levels of protein with maximum protein content in SPI (96.15%). The MPI sample, however, came out on top in terms of amino acid profile followed by FBI. Compared to SPI and LPI, it had the highest isoleucine content and higher methionine, valine, leucine, phenylalanine, and lysine. Moreover, MPI showed a median particle charge (-37.1 mV) compared to FPI, SPI, and LPI samples. MPI sample peak showed resistance to heat denaturation at a temperature greater than 200 °C when the DSC test was conducted. With respect to its rheological characteristics, it outperformed the other three protein isolates and exhibited the highest values of storage modulus G' and loss modulus G". Consequently, our study suggests that pulse-derived protein isolate mixture can be used as a unique type of nutritious dietary protein supplement. It could be a good nutritional alternative to proteins derived from animals.

Effect of Gamma Irradiation on Cannabinoid, Terpene, and Moisture Content of Cannabis Biomass.

In recent years, cannabis has been proposed and promoted not only as a medicine for the treatment of a variety of illnesses, but also as an industrial crop for different purposes. Being an agricultural product, cannabis inflorescences may be contaminated by environmental pathogens at high concentrations, which might cause health problems if not controlled. Therefore, limits have to be placed on the levels of aerobic bacteria as well as yeast and mold. To ensure the safety of cannabis plant material and related products, a remediation process has to be put in place. Gamma irradiation is a sterilization process mainly used for pharmaceuticals, foods, cosmetics, agricultural, and herbal products including cannabis plant material. This study was designed to determine the effect of irradiation on the microbial count as well as on the chemical and physical profiles of the cannabis biomass, particularly cannabinoids, terpenes, and moisture content. The full cannabinoid profile was measured by GC/FID and HPLC analysis, while terpene profile and moisture content were determined using GC/MS and Loss on Drying (LoD) methods, respectively. Analyses were conducted on the samples before and after gamma irradiation. The results showed that the minimum and maximum doses were 15 and 20.8 KiloGray (KGY), respectively. Total Aerobic Microbial Count (TAMC) and Total Yeast and Mold Count (TYMC) were determined. The study showed that irradiation has no effect on the cannabinoids and little effect on terpenes and moisture content, but it did result in the virtual sterilization of the plant material, as evidenced by the low levels of bacterial and fungal colony-forming units (CFUs) < 10 after gamma irradiation.