Transient downregulation of NR4A1 leads to impaired osteoblast differentiation through the TGF-ß pathway, and Elesclomol (STA-4783) rescues this phenotype.

Bone formation is regulated by numerous factors, such as transcription factors, cytokines, and extracellular matrix molecules. Human hormone nuclear receptors (hHNR) are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone. We found that an hHNR called NR4A1 was the most highly expressed after human MSC differentiation into osteoblasts by whole-genome microarray. NR4A1 knockout decreased the osteoblastic differentiation of hMSCs in terms of ALPL expression and key marker gene expression. Whole-genome microarray analysis further confirmed the decrease in key pathways when we knocked down NR4A1. Further studies with small molecule activators identified a novel molecule called Elesclomol (STA-4783), which could activate and enhance osteoblast differentiation. Elesclomol activation of hMSCs also induced the gene expression of NR4A1 and rescued the phenotype of NR4A1 KD. In addition, Elesclomol activated the TGF-ß pathway by regulating key marker genes. In conclusion, we first identified the role of NR4A1 in osteoblast differentiation and that Elesclomol is a positive regulator of NR4A1 through activation of the TGF-ß signalling pathway.

Effects of unpredictable chronic mild stress on the cellular redox state and mitochondrial energy homeostasis in rat adipose tissue: A comprehensive metabolic study.

Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty-four male Wistar rats (180-220 g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes of respiratory gases (VO2 & VCO2 ), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2 O2 ), lipid peroxides (LPO), t-protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α-KGDH, ICDH, SDH, MDH), respiratory chain complexes I-III, II-III, IV, the nicotinamide coenzymes NAD+ , NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+ , NADH, and ATP levels (p < .001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMS-subjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT.

Evaluation of psychological distress is essential for patients with locally advanced breast cancer prior to neoadjuvant chemotherapy: baseline findings from cohort study.

BACKGROUND: patients with locally advanced breast cancer (LABC) are often treated by neoadjuvant chemotherapy (NACT). This study aims to determine the prevalence of psychological distress and their sociodemographic and clinical factors in patients recently diagnosed with LABC and before NACT. METHODS: A total of 209 LABC patients without metastatic localization were recruited between 2021 and 2022 in the oncology hospital at Fez. A structured questionnaire and the Hospital Anxiety and Depression Scale were used. A descriptive analysis and linear model were performed. RESULTS: a mean age of participants was 47.43 ± 9.45 years. The prevalence of depression, anxiety and psychological distress among participants was 59.62% (95% CI: 52.61-33.34), 47.85% (95% CI: 40.91-54.85), and 65.07 (95% CI: 58.19-71.52) respectively. Depression was associated to age (< 50 years) (AOR = 2.19; 95% CI = 1.13-4.23) and health insurance (AOR = 3.64; 95% CI: 1.18-11.26). Anxiety was associated to age (< 50) (AOR = 2.21; 95% CI: 1.18-4.13) and right breast cancer (AOA = 2.01; 95% CI: 1.11-3.65). Psychological distress was associated to chronic illness (AOR = 2.78; 95% CI: 1.32-5.85) and lymph node status (AOR = 2.39; 95% CI: 1.26-4.57). CONCLUSIONS: Based on the high prevalence of depression and anxiety it appears opportune to treat psychological distress among LABC patient candidates for NACT. Each psychological intervention should take into account sociodemographic and clinical factors found associated in our study. Psychological therapeutic interventions are crucial for LABC patients as early as the time of diagnosis and through subsequent steps in NACT to improve their overall mental health.

Hepatoprotective effects of a chemically-characterized extract from artichoke (Cynara scolymus L.) against AFB1-induced toxicity in rats.

This study was conducted to investigate the protective potential of a pharmaceutically formulated capsule of artichoke leaf powder (ArLP) against aflatoxin B1 (AFB1)-induced hepatotoxicity in male albino rats. In the 42-day experiment, rats were divided into five equal groups: (i) control, treated with sterile water, (ii) treated with 4% DMSO as AFB1 vehicle, (iii) ArLP of 100 mg kg-1 bw, (iv) AFB1 of 72 µg kg-1 bw, and (v) AFB1 plus ArLP. Exposure of rats to AFB1 resulted in hepatotoxicity as manifested by the intensification of oxidative stress, production of free radicals and significant increase in the activity levels of liver function enzymes relative to the control. Significant reductions in both the enzymatic and non-enzymatic antioxidant markers as well as histopathological abnormalities in liver tissues were also observed. Notably, the combined administration of ArLP with AFB1 clearly reduced AFB1-mediated adverse effects leading to the normalization of most of these parameters back to control levels. These findings clearly highlight the potential benefits of artichoke dietary supplements as a safe and natural solution in counteracting the adverse hepatotoxic effects conferred by AFB1 exposure. Further research is warranted to fully dissect the biochemical and molecular mechanism of action of the observed artichoke-mediated hepatoprotection.

Volatile Constituents in Essential Oil from Leaves of Withania adpressa Coss. Ex Exhibit Potent Antioxidant and Antimicrobial Properties against Clinically-Relevant Pathogens.

Withania adpressa Coss. ex is a plant used in traditional medications. Antioxidant, antibacterial, and antifungal properties of the essential oil from leaves of Withania adpressa Coss ex. (EOW) were investigated. EOW was extracted using a Clevenger apparatus, and its volatile compounds were characterized by GC-MS. Antioxidant potency was determined using DPPH, FRAP, and TAC assays. Antibacterial effects were determined vs. Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Streptococcus pneumonia; while its antifungal efficacy was determined vs. Candida albicans, Aspergillus flavus, Aspergillus niger, and Fusarium oxysporum using the disc diffusion and minimum inhibitory concentration bioassays. A chromatographic analysis showed that EOW contained eight phytochemical compounds constituting 99.14% of the total mass of oil. Caryophyllene (24.74%), Longifolene (21.37%), δ-Cadinene (19.08%), and Carene (14.86%) were predominant compounds in EOW. The concentrations required to inhibit 50% of free radical (IC50) values of antioxidant activities of EOW were 0.031 ± 0.006 mg/mL (DPPH), 0.011 ± 0.003 mg/mL (FRAP), and 846.25 ± 1.07 mg AAE/g (TAC). Inhibition zone diameters of EOW vs. bacteria were 18.11 ± 0.5 mm (E. coli), 17.10 ± 0.42 mm (S. aureus), 12.13 ± 0.31 mm (K. pneumoniae), and 11.09 ± 0.47 mm (S. pneumoniae), while MIC values were 51 ± 3, 47 ± 5, 46 ± 3 and 31 ± 1 µg/mL, respectively. Inhibition zone diameters of EOW vs. fungi were 31.32 ± 1.32, 29.00 ± 1.5, 27.63 ± 2.10, and 24.51 ± s1.07 mm for A. flavus, C. albicans, F. oxysporum, and A. niger, respectively. MIC values were 8.41 ± 0.40, 28.04 ± 0.26, 9.05 ± 0.76, and 22.26 ± 0.55 µg/mL, respectively. Importantly, the highest dose of EOW (1 mg/mL) showed negligible (~5%) cytotoxicity against MCF-12, a normal human epithelial cell line derived from the mammary gland, thus underscoring its wide safety and selectivity against tested microbes. To sum it up, EOW has exhibited promising antioxidant and antimicrobial properties, which suggests potential to abrogate antibiotic resistance.

Assessment of impacts of industrial effluents on physico-chemical and microbiological qualities of irrigation water of the Fez Rriver, Morocco.

Global water consumption has grown twice as fast as the population. Wastewater is therefore a valuable and renewable source and provides additional water for priority uses. Wastewater can also be a source of pollution; thus, its physico-chemical and biological compositions can present major risks to the environment and human health. The objective of this study was to assess the status of irrigation waters in terms of salinization, accumulation of metallic elements, and microbiological contamination by parasites and pathogenic bacteria. The study focused on the surface water of Oued Fès used for irrigation located downstream of the industrial zone of Doukkarat and upstream of the industrial zone of Ain Noukbi (wastewater) before the confluence with the Oued Sebou, as well as on the treated wastewater of the wastewater treatment plant. The physico-chemical and microbiological analyses were carried out in two periods: summer and winter. Metals were analyzed by ICP-AES. The chemical and bacteriological quality of the wastewater and treated wastewater was found to be poor. These were characterized by organic pollution, including biodegradable pollutants, while upstream the organic residues were not biodegradables. COD, BOD5, Kjeldahl nitrogen, as well as chloride ion (Cl-) are above the standard values. The highest concentrations of Cd, at 850 µg/l, Cu, at 690 µg/l and Mn, at 470 µg/l, largely exceed the international standards and requirements. In addition to fecal contamination, characterized by total coliforms and thermo-tolerant coliforms, other pathogens were present, including helminth eggs, both in the wastewater and in the treated wastewater. Other pathogens, such as Vibrio cholera, were found at all three sites whether in winter or summer, with the exception of the downstream of Oued Fez in winter. As for Salmonella, it was present in treated wastewater during the winter only. The water used for irrigation upstream of Oued Fez and the treated wastewater have poor to very poor quality. Therefore, for a better use of these waters, it is necessary to ensure their regular treatment in order to minimize the impacts on the environment and human health.

Variation of phytochemical constituents, antioxidant, antibacterial, antifungal, and anti-inflammatory properties of Grantia aucheri (Boiss.) at different growth stages.

Phyto-natural products are deeply associated with ethno-medicinal practices with less or more scientific validation for curing many vital diseases. Thus, the present study was carried out to asses chemical constituents and bioactivities of Grantia aucheri Boiss at different growth stages (vegetative, flowering, and seeding). For this aim, the chemical composition of G. aucheri ethanolic extracts was analyzed by gas chromatography with mass spectrometry detection (GC-MS), their total phenolics, total flavonoids, total tannins, and total anthocyanins concentrations were also spectrophotometrically determined. Antifungal and antibacterial activities were determined against three pathogenic fungi and six human pathogenic bacteria. Furthermore, antioxidant activity (DPPH and ABTS scavenging) and anti-inflammatory activity (Human Red Blood Cell Stabilization Method) were evaluated. The highest content of total phenolics, total flavonoids, total tannins, and total anthocyanins were established in the extract of G. aucheri at its flowering stage. Such phyto-compounds as boranyl acetate, ß-himachalene and himachalol were major compounds found among 34 chemical constituents identified. The best antioxidant, anti-inflammatory, antifungal, and antibacterial activities were also found for this extract. Its phytochemicals presented bactericidal activities, mainly against Staphylococcus aureus, Bacillus subtilis, and Streptococcus pyogenes along with moderate fungicidal activity, however, it was less effective than the first one. Apart from antioxidant, antimicrobial, and anti-inflammatory activities, chemical constituents of G. aucheri may be potential alternative biomedical applications to reduce synthetic chemicals drugs.

Antioxidant and Antimicrobial Activities of Chemically-Characterized Essential Oil from Artemisia aragonensis Lam. against Drug-Resistant Microbes.

This study investigated the chemical composition, antioxidant and antimicrobial activity of essential oil extracted from Artemisia aragonensis Lam. (EOA). Hydrodistillation was employed to extract EOA. Gas chromatography with flame ionization detection (GC-FID) and gas chromatography-mass spectrometry analyses (GC-MS) were used to determine the phytochemical composition of EOA. Antioxidant potential was examined in vitro by use of three tests: 2.2-diphenyl-1-picrilhidrazil (DPPH), ferric reducing activity power (FRAP) and total antioxidant capacity assay (TAC). Agar diffusion and microdilution bioassays were used to assess antimicrobial activity. GC/MS and GC-FID detected 34 constituents in the studied EOA. The major component was Camphor (24.97%) followed by Borneol (13.20%), 1,8 Cineol (10.88%), and Artemisia alcohol (10.20%). EOA exhibited significant antioxidant activity as measured by DPPH and FRAP assays, with IC50 and EC50 values of 0.034 ± 0.004 and 0.118 ± 0.008 mg/mL, respectively. EOA exhibited total antioxidant capacity of 7.299 ± 1.774 mg EAA/g. EOA exhibited potent antibacterial activity as judged by the low minimum inhibitory concentration (MIC) values against selected clinically-important pathogenic bacteria. MIC values of 6.568 ± 1.033, 5.971 ± 1.033, 7.164 ± 0.0 and 5.375 ± 0.0 µg/mL were observed against S. aureus, B. subtills, E. coli 97 and E. coli 57, respectively. EOA displayed significant antifungal activity against four strains of fungi: F. oxysporum, C. albicans, A. flavus and A. niger with values of 21.50 ± 0.43, 5.31 ± 0.10, 21.50 ± 0.46 and 5.30 ± 0.036 µg/mL, respectively. The results of the current study highlight the importance of EOA as an alternative source of natural antioxidant and antibacterial drugs to combat antibiotic-resistant microbes and free radicals implicated in the inflammatory responses accompanying microbial infection.

Antioxidant, Antimicrobial, and Insecticidal Properties of a Chemically Characterized Essential Oil from the Leaves of Dittrichia viscosa L.

Since some synthetic insecticides cause damage to human health, compounds in plants can be viable alternatives to conventional synthetic pesticides. Dittrichia viscosa L. is a perennial Mediterranean plant known to possess biological activities, including insecticidal properties. The chemical composition of an essential oil (EOD) from D. viscosa, as well as its antioxidant, antimicrobial, and insecticidal effects on the cowpea weevil (Callosobruchus maculatus) were determined. Forty-one volatile compounds were identified in EOD, which accounted for 97.5% of its constituents. Bornyl acetate (41%) was a major compound, followed by borneol (9.3%), α-amorphene (6.6%), and caryophyllene oxide (5.7%). EOD exhibited significant antioxidant activity in all tests performed, with an IC50 of 1.30 ± 0.05 mg/mL in the DPPH test and an EC50 equal to 36.0 ± 2.5 mg/mL in the FRAP assay. In the phosphor-molybdenum test, EOD results ranged from 39.81 ± 0.7 to 192.1 ± 0.8 mg AAE/g E. EOD was active on E. coli (9.5 ± 0.5 mm), S. aureus (31.0 ± 1.5 mm), C. albicans (20.4 ± 0.5 mm), and S. cerevisiae (28.0 ± 1.0 mm), with MICs ranging from 0.1 mg/mL to 3.3 mg/mL. We found that 1 µL of EOD caused 97.5 ± 5.0% insect mortality after 96 h in the inhalation test and 60.0 ± 8.3% in the ingestion assay. The median lethal concentration (LC50) was 7.8 ± 0.3 µL EO/L, while the effective concentration in the ingestion test (LC50) was 15.0 ± 2.1 µL EO/L. We found that 20 µL of EOD caused a reduction of more than 91% of C. maculatus laid eggs.

Efforts in Bioprospecting Research: A Survey of Novel Anticancer Phytochemicals Reported in the Last Decade.

Bioprospecting natural products to find prominent agents for medical application is an area of scientific endeavor that has produced many clinically used bioactive compounds, including anticancer agents. These compounds come from plants, microorganisms, and marine life. They are so-called secondary metabolites that are important for a species to survive in the hostile environment of its respective ecosystem. The kingdom of Plantae has been an important source of traditional medicine in the past and is also enormously used today as an exquisite reservoir for detecting novel bioactive compounds that are potent against hard-to-treat maladies such as cancer. Cancer therapies, especially chemotherapies, are fraught with many factors that are difficult to manage, such as drug resistance, adverse side effects, less selectivity, complexity, etc. Here, we report the results of an exploration of the databases of PubMed, Science Direct, and Google Scholar for bioactive anticancer phytochemicals published between 2010 and 2020. Our report is restricted to new compounds with strong-to-moderate bioactivity potential for which mass spectroscopic structural data are available. Each of the phytochemicals reported in this review was assigned to chemical classes with peculiar anticancer properties. In our survey, we found anticancer phytochemicals that are reported to have selective toxicity against cancer cells, to sensitize MDR cancer cells, and to have multitarget effects in several signaling pathways. Surprisingly, many of these compounds have limited follow-up studies. Detailed investigations into the synthesis of more functional derivatives, chemical genetics, and the clinical relevance of these compounds are required to achieve safer chemotherapy.

Comparative Study of Antimicrobial Activity of Silver, Gold, and Silver/Gold Bimetallic Nanoparticles Synthesized by Green Approach.

Nanotechnology is one of the most recent technologies. It is uncertain whether the production of small-size nanoparticles (NPs) can be achieved through a simple, straightforward, and medicinally active phytochemical route. The present study aimed to develop an easy and justifiable method for the synthesis of Ag, Au, and their Ag/Au bimetallic NPs (BNPs) by using Hippeastrum hybridum (HH) extract, and then to investigate the effects of Ag, Au, and their Ag/Au BNPs as antimicrobial and phytotoxic agents. Ag, Au, and their Ag/Au BNPs were characterized by UV-visible spectroscopy, FT-IR spectroscopy, XRD, EDX, and SEM analysis. XRD analysis conferring to the face of face-centered cubic crystal structure with an average size of 13.3, 10.72, and 8.34 nm of Ag, Au, and Ag/Au BNPs, respectively. SEM showed that Ag, Au, and Ag/Au BNPs had spherical morphologies, with calculated nano measurements of 40, 30, and 20 nm, respectively. The EDX analysis confirmed the composition of elemental Ag signal of the HH-AgNPs with 22.75%, Au signal of the HH-AuNPs with 48.08%, Ag signal with 12%, and Au signal with 38.26% of the Ag/Au BNPs. The Ag/Au BNPs showed an excellent antimicrobial efficacy against Gram-positive Staphylococcus aureus, Actinomycetes meriye, Bacillus cereus, Streptococcus pyogenes, Methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Streptococcus pneumonia, and Gram-negative Klebsiella pneumonia, Escherichia coli, and Serratia marcescens bacterial strains, as well as against three fungal strains (Aspergillus niger, Aspergillus fumigatus, and Aspergillus flavus) compared to HH extract, HH-AgNPs, and HH-AuNPs. However, further investigations are recommended to be able to minimize potential risks of application.

Solanum elaeagnifolium Var. Obtusifolium (Dunal) Dunal: Antioxidant, Antibacterial, and Antifungal Activities of Polyphenol-Rich Extracts Chemically Characterized by Use of In Vitro and In Silico Approaches.

The present work was designed to study the chemical composition and the antioxidant and antimicrobial properties of fruits (SFr) and leaf (SF) extracts from Solanum elaeagnifolium var. obtusifolium (Dunal) Dunal (S. elaeagnifolium). The chemical composition was determined using HPLC-DAD analysis. Colorimetric methods were used to determine polyphenols and flavonoids. Antioxidant capacity was assessed with DPPH, TAC, and FRAP assays. Antimicrobial activity was assessed using disk diffusion and microdilution assays against two Gram (+) bacteria (Staphylococcus aureus ATCC-6633 and Bacillus subtilis DSM-6333) and two Gram (-) bacteria (Escherichia coli K-12 and Proteus mirabilis ATCC-29906), while the antifungal effect was tested vs. Candida albicans ATCC-1023. By use of in silico studies, the antioxidant and antimicrobial properties of the studied extracts were also investigated. HPLC analysis showed that both fruits and leaf extracts from S. elaeagnifolium were rich in luteolin, quercetin, gallic acid, and naringenin. Both SFr and SF generated good antioxidant activity, with IC50 values of 35.15 ± 6.09 µg/mL and 132.46 ± 11.73 µg/mL, respectively. The EC50 of SFr and SF was 35.15 ± 6.09 µg/mL and 132.46 ± 11.73 µg/mL, respectively. SFr and SF also showed a good total antioxidant capacity of 939.66 ± 5.01 µg AAE/and 890.1 ± 7.76 µg AAE/g, respectively. SFr had important antibacterial activity vs. all tested strains-most notably B. subtilis DSM-6333 and E. coli, with MICs values of 2.5 ± 0.00 mg/mL and 2.50 ± 0.00 mg/mL, respectively. SFr demonstrated potent antifungal activity against C. albicans, with an inhibition diameter of 9.00 ± 0.50 mm and an MIC of 0.31 ± 0.00 mg/mL. The in silico approach showed that all compounds detected in SFr and SF had high activity (between -5.368 and 8.416 kcal/mol) against the receptors studied, including NADPH oxidase, human acetylcholinesterase, and beta-ketoacyl-[acyl carrier protein] synthase.

Isolated and Combined Effect of Age and Gender on Neutrophil-Lymphocyte Ratio in the Hyperglycemic Saudi Population.

Inflammation is pivotal to the pathogenesis of diabetes mellitus (DM), but pathological alterations of the neutrophil−lymphocyte ratio (NLR), an emerging inflammatory index in DM management, remains understudied. The aim of this study is to examine the relationship between NLR and glycemic control in the Saudi population. Gender, age, WBC count, and fasting blood glucose (FBG) were obtained from Al-Borg Medical Laboratories for 14,205 subjects. Means, prevalence, risk measures, and the diagnostic accuracy of elevated NLR and hyperglycemia (HG) were evaluated. Subjects with elevated NLR (>3) had significantly higher FBG (105.10 ± 0.33 vs. 114.0 ± 2.81) and NLR was significantly elevated in impaired fasting glycemia (IFG; 1.21 ± 0.01 vs. 1.25 ± 0.01) and HG (1.21 ± 0.01 vs. 1.39 ± 0.02). Elevations of NLR in HG but not in IFG persisted across all age groups except young males and elderly females. The prevalence of elevated NLR in hyperglycemic subjects was 4.12% compared to 2.16% in subjects with normal FBG. HG was more prevalent in subjects with elevated NLR (17.33% vs. 12.46%) who had a relative risk (RR) of 1.68 (95% CI = 1.38−2.06, p < 0.0001) and an odds ratio (OR) of 1.94 (95% CI = 1.48−2.56, p < 0.0001) to be hyperglycemic. Nevertheless, NLR failed to discriminate individuals with normal FBG from those with HG based on ROC curve analysis. Pathological fluctuations in NLR may serve as supportive evidence in DM management.

Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects.

The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC50 values obtained were 5.7-21.3 and 5.8-37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h the highest cytotoxicity with IC50 value of 19.2µg/mL relative to doxorubicin (IC50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.

Specific Cytotoxic Effects of Parasporal Crystal Proteins Isolated from Native Saudi Arabian Bacillus thuringiensis Strains against Cervical Cancer Cells.

Currently, global efforts are being intensified towards the discovery of local Bacillus thuringiensis (Bt) isolates with unique anticancer properties. Parasporins (PS) are a group of Bt non-insecticidal crystal proteins with potential and specific in vitro anticancer activity. However, despite the significant therapeutic potential of PS-producing Bt strains, our current knowledge on the effects of these proteins is limited. Hence, the main objective of this study was to screen Bt-derived parasporal toxins for cytotoxic activities against colon (HT-29) and cervical (HeLa) cancerous cell lines. Nine non-larvicidal and non-hemolytic Bt strains, native to Saudi Arabia, were employed for the isolation of their parasporal toxins. 16S rDNA sequencing revealed a 99.5% similarity with a reference Bt strain. While PCR screening results indicated the absence of selected Cry (Cry4A, Cry4B, Cry10 and Cry11), Cyt (Cyt1 and Cyt2) and PS (PS2, PS3 and PS4) genes, it concluded presence of the PS1 gene. SDS-PAGE analysis revealed that proteolytically-cleavaged PS protein profiles exhibit patterns resembling those observed with PS1Aa1, with major bands at 56 kDa and 17 kDa (Bt7), and 41 kDa and 16 kDa (Bt5). Solubilized and trypsinized PS proteins from all Bt strains exhibited a marked and dose-dependent cytotoxicity against HeLa cancerous cells but not against HT-29 cells. IC50 values ranged from 3.2 (Bt1) to 14.2 (Bt6) with an average of 6.8 µg/mL. The observed cytotoxicity of PS proteins against HeLa cells was specific as it was not evident against normal uterus smooth muscle cells. RT-qPCR analysis revealed the overexpression of caspase 3 and caspase 9 by 3.7, and 4.2 folds, respectively, indicative of the engagement of intrinsic pathway of apoptosis. To the best of our knowledge, this is the first report exploring and exploiting the versatile repertoire of Saudi Arabian environmental niches for the isolation of native and possibly novel Saudi Bt strains with unique and specific anticancer activity. In conclusion, native Saudi Bt-derived PS proteins might have a potential to join the arsenal of natural anticancer drugs.

Seasonal concentrations of lead in outdoor and indoor dust and blood of children in Riyadh, Saudi Arabia.

Because detrimental effects of exposure to lead (Pb) on human health have been observed, we previously investigated concentrations of Pb in water supplies and blood of adult residents of Riyadh, Saudi Arabia. The objectives of the present study were to: (1) examine seasonal rates of deposition of Pb in dust in several areas of Riyadh city, (2) measure concentrations of Pb in both outdoor and indoor dust, (3) compare concentrations of Pb in dust in Riyadh with those reported for other cities, and (4) quantify Pb in blood of children living in Riyadh. Mean, monthly deposition of PB in outdoor dust was 4.7 × 10(1) ± 3.6 tons km(-2), with a mean Pb concentration of 2.4 × 10(2) ± 4.4 × 10(1) µg/g. Mean, monthly deposition of Pb in indoor dust was 2.7 ± 0.70 tons km(-2), with a mean concentration of 2.9 × 10(1) ± 1.5 × 10(1) µg Pb/g. There was a significant (P < 0.01) correlation between concentrations of Pb in outdoor and indoor dust. There was no correlation between concentrations of Pb in indoor dust and that in blood of children of Riyadh, whereas there was a weakly significant (P < 0.05) correlation between concentrations of Pb in outdoor dust and that in blood of children. The mean (±SD) concentration of Pb in blood of children in Riyadh was 5.2 ± 1.7, with a range of 1.7-1.6 × 10(1) µg/dl. Concentrations of Pb in blood of 17.8 % of children in Riyadh were greater than 10 µg/dl, which is the CDC's level of concern.

Kinase inhibitors: 20 years of success and many new challenges and recent trends in their patents.

INTRODUCTION: Protein kinases (PKs) play key roles in cellular signaling and regulation cascades and therefore are listed among the most investigated enzymes with the intent to develop drugs that are able to modulate their catalytic features. Specifically, PKs are involved in chronic diseases of large impact in the society such as cancers and neurodegeneration. Since the approval of Fasudil for the management of cerebral vasospasm, frantic efforts are currently ongoing for the development of selective PK-modulating agents. AREAS COVERED: A selection of the most relevant patents in the European Patent Office for biomedical innovation and/or industrial development covering the years 2020-2023 on PK modulators either of the antibody and small-molecule type is reported. In addition to the examined patents, we also reported the contributions claiming the use of antibody-targeted PKs for lab bench identification kits. EXPERT OPINION: The field of PK modulators for biomedical purposes is particularly crowded with contributions, making it rich in valuable information for the development of potential drugs. An emerging frontier is represented by PK activators that aims to complement the use of PK inhibitors with the final intent of finely adjusting any PK-related disruption responsible for triggering any disease.

Lipid-based Nutritional Supplement Impact on Energy Intake, Appetite, Glucose and Insulin Levels in Under-Weight Pregnant and Lactating Women with Preeclampsia.

OBJECTIVE: To investigate the response of nutritional supplement (LNS-PLW) on appetite score, energy intake, insulin and glucose levels in preeclamptic women. DESIGN & PARTICIPANTS: Sixty under-weight preeclamptic primigravida were divided into two groups randomly and provided LNS-PLW/Placebo in the fasted state. Blood samples were collected at fasting state, after 30mins of supplementation, "ad libitum buffet" breakfast and lunch for glucose and insulin levels. RESULTS: Total energy intake was higher significantly in the LNS-PLW group, although during breakfast it was significantly reduced. The insulin and glucose concentration was significantly increased after 30min of supplementation in the LNS-PLW group. CONCLUSION: Intake of the LNS-PLW by pre-eclamptic women had short-term suppression on subsequent meal but improved total energy intake during trial.

In vivo and in silico studies of the effects of oil extracted from Cannabis sativa L. seeds on healing of burned skin wounds in rats.

Introduction: This study investigates the potential effects of cannabis seed oil (CSO) on the wound healing process. The aim was to assess the efficacy of CSO in treating skin wounds using an animal model and to explore its anti-inflammatory properties through in silico analysis. Methods: Eighteen male albino Wistar rats, weighing between 200 and 250 g, were divided into three groups: an untreated negative control group, a group treated with the reference drug silver sulfadiazine (SSD) (0.01 g/mL), and a group treated topically with CSO (0.962 g/mL). The initial wound diameter for all groups was 1 cm. In silico studies were conducted using Maestro 11.5 to evaluate the anti-inflammatory effects of phytoconstituents against cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Results: CSO and SSD treatments led to a significant reduction (p <0.05) in the size of burned skin wounds by day 5, with contraction rates of 53.95% and 45.94%, respectively, compared to the untreated negative control group. By day 15, wounds treated with CSO and SSD had nearly healed, showing contraction rates of 98.8% and 98.15%, respectively. By day 20, the wounds treated with CSO had fully healed (100%), while those treated with SSD had almost completely healed, with a contraction rate of 98.97%. Histological examination revealed granulated tissue, neo-blood vessels, fibroblasts, and collagen fibers in wounds treated with CSO. In silico studies identified arachidic acid, γ-linolenic acid, and linolenic acid as potent inhibitors of COX-1 and COX-2. Serum biochemical parameters indicated no significant changes (p > 0.05) in liver and kidney function in rats treated with CSO, whereas a significant increase (p < 0.01) in ALAT level was observed in rats treated with SSD. Discussion: The findings demonstrate that CSO has a promising effect on wound healing. The CSO treatment resulted in significant wound contraction and histological improvements, with no adverse effects on liver and kidney function.However, the study's limitations, including the small sample size and the need for detailed elucidation of CSO's mechanism of action, suggest that further research is necessary. Future studies should focus on exploring the molecular pathways and signaling processes involved in CSO's pharmacological effects.