Knowledge of cervical cancer, human papillomavirus (HPV), and acceptance of the HPV vaccine among parents of daughters in Riyadh, Saudi Arabia.

BACKGROUND: Cervical cancer is the eighth most prevalent cancer among women nationwide, with 358 new cases reported annually. One of the strategies to prevent it is getting vaccinated against the human papillomavirus (HPV), the leading cause of this cancer. METHODS: A survey-based cross-sectional study was conducted in Riyadh, Saudi Arabia, to evaluate the acceptance of the HPV vaccine among parents of daughters and their knowledge of three domains: cervical cancer, HPV, and the HPV vaccine. RESULTS: 390 parents participated in the study, with 88.2% female, 39.74% of the participants aged between 36-62 years old, and 62.56% holding a bachelor's degree or above. Parents were more aware of cervical cancer (78.97%), followed by HPV (50%) and the HPV vaccine (41.28%). Awareness levels about cervical cancer were significantly different among males and females, while awareness of HPV and the HPV vaccine was significantly associated with parents' education levels. For instance, parents with a bachelor's degree or higher (54.9%) demonstrated greater awareness of HPV compared to parents with a high school diploma (41.9%) or a middle school diploma or less (41.5%). The overall participants' knowledge scores in all three domains were poor, with an average below 50%. 60% of parents believed their daughters should receive the HPV vaccine. CONCLUSION: More than half of the study participants are willing to vaccinate their daughters with the HPV vaccine despite their poor knowledge of the assessed domains. Awareness levels of HPV and the HPV vaccine are associated with education levels. We believe raising awareness among parents is necessary to improve the acceptance level of the HPV vaccine.

Protective Role of Betulinic Acid against Cisplatin-Induced Nephrotoxicity and Its Antibacterial Potential toward Uropathogenic Bacteria.

Acute kidney injury (AKI) is one of the major side effects of cisplatin, a remarkable anticancer agent. Therefore, there is a growing need to find an agent that could mitigate cisplatin-induced nephrotoxicity. Betulinic acid (BA) is a natural compound isolated from Silene succulenta Forssk for the first time, with miraculous biological activities and no reports of its effect on the nephrotoxicity induced by cisplatin. Mice received BA orally with doses of 30 and 50 mg/kg before the intraperitoneal injection of cisplatin. Betulinic acid was found to decrease serum levels of creatinine and tissue levels of NGAL and kidney injury molecule (KIM-1) and improve the histological changes in the kidney. In addition, BA decreased the oxidative stress marker malondialdehyde (MDA), increased superoxide dismutase (SOD) antioxidative activity and suppressed the intensity of IL-1B and NFкB immuno-staining. Interestingly, betulinic acid enhanced autophagy by increasing beclin 1, ATG5, and LC3II and decreasing p62 expressions. Thus, our findings suggest betulinic acid as a potential agent that may protect from acute kidney injury by targeting inflammation, oxidative stress, and autophagy processes. Novel drugs are needed to combat the spreading of multidrug resistance between pathogenic bacteria, especially uropathogenic isolates. So, we elucidated the antibacterial properties of BA on Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Betulinic acid had minimum inhibitory concentration values (128 to 512 µg/mL). In addition, it adversely affected the membrane integrity of the tested isolates. Accordingly, betulinic acid should be clinically investigated in the future for urinary tract diseases.

The potential beneficial role of Ginkgetin in doxorubicin-induced hepatotoxicity: Elucidating the underlying claim.

Doxorubicin (DOX) is a widely used chemotherapeutic agent for various tumors treatment; apart from its chemotherapeutic activity, the traditional usage of DOX has been limited by its adverse effects on multiple organs, mainly hepatotoxicity. The molecular mechanisms underlying DOX hepatotoxicity are mainly due to the production of reactive oxygen species (ROS) inducing oxidative stress, diminishing antioxidant enzymes, apoptosis, inflammation, and mitochondrial dysfunction. Thus, there is an urgent need to develop a therapy that minimizes DOX hepatotoxicity and widens its use in various types of cancers without fear of its serious hepatotoxicity. Ginkgetin (GINK), a natural biflavonoid, exhibits diverse actions, including promising free radical scavenging, antioxidant, and anti-inflammatory activities. So, this study's objectives were to determine whether GINK could mitigate DOX's hepatotoxic effects and look into a putative hepatoprotective molecular pathway. Mice were divided into five groups: Normal control, control GINK 100, Untreated DOX group, and DOX groups treated with GINK (50 and 100 mg/kg) intraperitoneally daily for four days before DOX administration and an additional three days afterward. GINK 100 pretreatment showed marked protection from DOX hepatotoxicity and also attenuation of histopathological structural alterations. These outcomes were corroborated biochemically by a considerable decrease in alanine aminotransferases, aspartate aminotransferase, and alkaline phosphatase levels. GINK significantly augmented silent information regulator 1 and nuclear translocation of NF-E2-related factor 2 and repressed the expression and protein levels of forkhead box protein O1, inducible nitric oxide synthase, and P53 relative to DOX group. GINK alleviated oxidative stress and induced significant anti-inflammatory effects via suppression of interleukin-6, nuclear factor Kabba B, and iNOS respectively. This study is the first to investigate GINK's potentially beneficial effects in acute DOX hepatotoxicity, possibly exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects by modulation of Sirt1/FOXO-1/NF-κB Signal.

Silver Nanoparticles Prepared Using Encephalartos laurentianus De Wild Leaf Extract Have Inhibitory Activity against Candida albicans Clinical Isolates.

Candida albicans is a major human opportunistic pathogen causing infections, which range from cutaneous to invasive systemic infections. Herein, the antifungal and anti-biofilm potential of silver nanoparticles (AgNPs) green synthesized in the presence of Encephalartos laurentianus leaf extract (ELLE) were investigated. The bioactive chemicals of ELLE, including phenolics, flavonoids, and glycosides were identified and quantified for the first time. AgNPs showed minimum inhibitory concentration (MIC) values against C. albicans clinical isolates ranging from 8 to 256 µg/mL. In addition, AgNPs significantly decreased biofilm formation. The impact of AgNPs on the expression of the genes encoding biofilm formation was assessed using qRT-PCR. AgNPs had a beneficial role in the macroscopic wound healing, and they resulted in complete epithelization without any granulation tissue or inflammation. Treatment with AgNPs resulted in negative immunostaining of tumor necrosis factor-α. The levels of the inflammation markers, interleukin-6 and interleukin-1ß, significantly decreased (p < 0.05) in the AgNPs-treated group. There was also a pronounced increase in the gene expression of fibronectin and platelet-derived growth factor in the wound tissues. Thus, AgNPs synthesized using ELLE may be a promising antifungal and wound healing agent.

Potential cardioprotective effects of Amentoflavone in doxorubicin-induced cardiotoxicity in mice.

Doxorubicin (DOX) is an available chemotherapeutic drug for treating various tumors. However, its effectiveness is limited by cardiotoxicity. Amentoflavone (AMF), a natural biflavonoid separated from Cycas thouarsii ethyl acetate fraction, displays promising anticancer, anti-inflammatory, and antioxidant effects. Thus, our research aims to explore whether AMF could boost cardioprotective effects against DOX cardiotoxicity and reveal the potential underlying mechanisms of cardioprotection. Mice were classified into four groups; Normal control, Untreated DOX group, and DOX groups treated with AMF (40 and 80 mg/kg, respectively) intraperitoneal injection daily for four days before doxorubicin administration and for additional three days following DOX administration to assess cardiotoxicity. Echocardiography showed that AMF 80 treated group was protected from DOX cardiotoxicity. Additionally, it alleviated histopathological structural alterations and effectively restored heart weight and body weight ratio. These effects were confirmed biochemically by a substantially reduced serum creatine kinase-MB (CK-MB) and aspartate aminotransferase (AST) levels. AMF effectively restored nuclear respiratory factor-1(NRF-1), mitochondrial transcription factor A (TFAM), and normalized heat shock protein - 27(HSP-27) expression levels compared to the DOX group. Moreover, AMF mitigated oxidative stress conditions and significantly suppressed NADPH oxidase (NOX) expression levels. It also showed significant anti-inflammatory effects via suppressing interleukin-6 (IL-6) expression and decreasing nuclear factor Kabba B (NF-κb) immune-staining. In addition, AMF markedly reduced FAS ligand (FASL) expression and p53 immune staining in cardiac tissue. This study is the first for the in vivo potential beneficial effects of AMF against acute DOX cardiotoxicity, possibly via exerting antioxidant, anti-inflammatory, and anti-apoptotic effects and restoring mitochondrial function.

SULT genetic polymorphisms: physiological, pharmacological and clinical implications.

INTRODUCTION: Cytosolic sulfotransferases (SULTs)-mediated sulfation is critically involved in the metabolism of key endogenous compounds, such as catecholamines and thyroid/steroid hormones, as well as a variety of drugs and other xenobiotics. Studies performed in the past three decades have yielded a good understanding about the enzymology of the SULTs and their structural biology, phylogenetic relationships, tissue/organ-specific/developmental expression, as well as the regulation of the SULT gene expression. An emerging area is related to the functional impact of the SULT genetic polymorphisms. AREAS COVERED: The current review aims to summarize our current knowledge about the above-mentioned aspects of the SULT research. An emphasis is on the information concerning the effects of the polymorphisms of the SULT genes on the functional activity of the SULT allozymes and the associated physiological, pharmacological, and clinical implications. EXPERT OPINION: Elucidation of how SULT SNPs may influence the drug-sulfating activity of SULT allozymes will help understand the differential drug metabolism and eventually aid in formulating personalized drug regimens. Moreover, the information concerning the differential sulfating activities of SULT allozymes toward endogenous compounds may allow for the development of strategies for mitigating anomalies in the metabolism of these endogenous compounds in individuals with certain SULT genotypes.

Effects of genetic polymorphisms on the sulfation of doxorubicin by human SULT1C4 allozymes.

Doxorubicin is a chemotherapeutic drug widely utilized in cancer treatment. An enzyme critical to doxorubicin metabolism is the cytosolic sulfotransferase (SULT) SULT1C4. This study investigated the functional impact of SULT1C4 single nucleotide polymorphisms (SNPs) on the sulfation of doxorubicin by SULT1C4 allozymes. A comprehensive database search was performed to identify various SULT1C4 SNPs. Ten nonsynonymous SULT1C4 SNPs were selected, and the corresponding cDNAs, packaged in pGEX-2TK expression vector, were generated via site-directed mutagenesis. Respective SULT1C4 allozymes were bacterially expressed and purified by affinity chromatography. Purified SULT1C4 allozymes, in comparison with the wild-type enzyme, were analysed for sulphating activities towards doxorubicin and 4-nitrophenol, a prototype substrate. Results obtained showed clearly differential doxorubicin-sulphating activity of SULT1C4 allozymes, implying differential metabolism of doxorubicin through sulfation in individuals with distinct SULT1C4 genotypes.

Impact of Human SULT1E1 Polymorphisms on the Sulfation of 17ß-Estradiol, 4-Hydroxytamoxifen, and Diethylstilbestrol by SULT1E1 Allozymes.

BACKGROUND AND OBJECTIVES: Previous studies have revealed that sulfation, as mediated by the estrogen-sulfating cytosolic sulfotransferase (SULT) SULT1E1, is involved in the metabolism of 17ß-estradiol (E2), 4-hydroxytamoxifen (4OH-tamoxifen), and diethylstilbestrol in humans. It is an interesting question whether the genetic polymorphisms of SULT1E1, the gene that encodes the SULT1E1 enzyme, may impact on the metabolism of E2 and these two drug compounds through sulfation. METHODS: In this study, five missense coding single nucleotide polymorphisms of the SULT1E1 gene were selected to investigate the sulfating activity of the coded SULT1E1 allozymes toward E2, 4OH-tamoxifen, and diethylstilbestrol. Corresponding cDNAs were generated by site-directed mutagenesis, and recombinant SULT1E1 allozymes were bacterially expressed, affinity-purified, and characterized using enzymatic assays. RESULTS: Purified SULT1E1 allozymes were shown to display differential sulfating activities toward E2, 4OH-tamoxifen, and diethylstilbestrol. Kinetic analysis revealed further distinct Km (reflecting substrate affinity) and Vmax (reflecting catalytic activity) values of the five SULT1E1 allozymes with E2, 4OH-tamoxifen, and diethylstilbestrol as substrates. CONCLUSIONS: Taken together, these findings highlighted the significant differences in E2-, as well as the drug-sulfating activities of SULT1E1 allozymes, which may have implications in the differential metabolism of E2, 4OH-tamoxifen, and diethylstilbestrol in individuals with different SULT1E1 genotypes.

Effect of SULT2B1 genetic polymorphisms on the sulfation of dehydroepiandrosterone and pregnenolone by SULT2B1b allozymes.

Pregnenolone and dehydroepiandrosterone (DHEA) are hydroxysteroids that serve as biosynthetic precursors for steroid hormones in human body. SULT2B1b has been reported to be critically involved in the sulfation of pregnenolone and DHEA, particularly in the sex steroid-responsive tissues. The current study was designed to investigate the impact of the genetic polymorphisms of SULT2B1 on the sulfation of DHEA and pregnenolone by SULT2B1b allozymes. Ten SULT2B1b allozymes previously prepared were shown to exhibit differential sulfating activities toward DHEA and pregnenolone in comparison to the wild-type enzyme. Kinetic studies revealed further significant changes in their substrate-binding affinity and catalytic activity toward DHEA and pregnenolone. Taken together, these results indicated clearly a profound effect of SULT2B1 genetic polymorphisms on the sulfating activity of SULT2B1b allozymes toward DHEA and pregnenolone, which may have implications in inter-individual variations in the homeostasis of these two important steroid precursors.

Impact of SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of phenylephrine and salbutamol by human SULT1A3 allozymes.

OBJECTIVES: Phenylephrine and salbutamol are drugs that are used widely to treat diseases/disorders, such as nasal congestion, hypotension, and asthma, in individuals of different age groups. Human cytosolic sulfotransferase (SULT) SULT1A3 has been shown to be critically involved in the metabolism of these therapeutic agents. This study was carried out to investigate the effects of single nucleotide polymorphisms of human SULT1A3 and SULT1A4 genes on the sulfation of phenylephrine and salbutamol by SULT1A3 allozymes. MATERIALS AND METHODS: Wild-type and SULT1A3 allozymes, prepared previously by site-directed mutagenesis in conjunction with bacterial expression and affinity purification, were analyzed for sulfating activity using an established assay procedure. RESULTS: Purified SULT1A3 allozymes, in comparison with the wild-type enzyme, showed differential sulfating activities toward phenylephrine and salbutamol. Kinetic studies showed further significant variations in their substrate-binding affinity and catalytic activity toward phenylephrine and salbutamol. CONCLUSION: The results obtained showed clearly the differential enzymatic characteristics of SULT1A3 allozymes in mediating the sulfation of phenylephrine and salbutamol. This information may contribute toward a better understanding of the pharmacokinetics of these two drugs in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.

Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen,O-desmethylnaproxen, and tapentadol.

BACKGROUND: Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes. METHODS: Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure. RESULTS: Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP. CONCLUSION: Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes.

Effects of genetic polymorphisms on the sulfation of dehydroepiandrosterone and pregnenolone by human cytosolic sulfotransferase SULT2A1.

The cytosolic sulfotransferase (SULT) SULT2A1 is known to mediate the sulfation of DHEA as well as some other hydroxysteroids such as pregnenolone. The present study was designed to investigate how genetic polymorphisms of the human SULT2A1 gene may affect the sulfation of DHEA and pregnenolone. Online databases were systematically searched to identify human SULT2A1 single nucleotide polymorphisms (SNPs). Of the 98 SULT2A1 non-synonymous coding SNPs identified, seven were selected for further investigation. Site-directed mutagenesis was used to generate cDNAs encoding these seven SULT2A1 allozymes, which were expressed in BL21 Escherichia coli cells and purified by glutathione-Sepharose affinity chromatography. Enzymatic assays revealed that purified SULT2A1 allozymes displayed differential sulfating activity toward both DHEA and pregnenolone. Kinetic analyses showed further differential catalytic efficiency and substrate affinity of the SULT2A1 allozymes, in comparison with wild-type SULT2A1. These findings provided useful information concerning the effects of genetic polymorphisms on the sulfating activity of SULT2A1 allozymes.

Effects of human SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of acetaminophen and opioid drugs by the cytosolic sulfotransferase SULT1A3.

Sulfoconjugation has been shown to be critically involved in the metabolism of acetaminophen (APAP), morphine, tapentadol and O-desmethyl tramadol (O-DMT). The objective of this study was to investigate the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the sulfating activity of SULT1A3 allozymes toward these analgesic compounds. Twelve non-synonymous coding SNPs (cSNPs) of SULT1A3/SULT1A4 were investigated, and the corresponding cDNAs were generated by site-directed mutagenesis. SULT1A3 allozymes, bacterially expressed and purified, exhibited differential sulfating activity toward each of the four analgesic compounds tested as substrates. Kinetic analyses of SULT1A3 allozymes further revealed significant differences in binding affinity and catalytic activity toward the four analgesic compounds. Collectively, the results derived from the current study showed clearly the impact of cSNPs of the coding genes, SULT1A3 and SULT1A4, on the sulfating activity of the coded SULT1A3 allozymes toward the tested analgesic compounds. These findings may have implications in the pharmacokinetics as well as the toxicity profiles of these analgesics administered in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.

On the role of genetic polymorphisms in the sulfation of cholesterol by human cytosolic sulphotransferase SULT2B1b.

Sulphated cholesterol, like its unsulphated counterpart, is known to be biologically active and serves a myriad of biochemical/physiological functions. Of the 13 human cytosolic sulphotransferases (SULTs), SULT2B1b has been reported as the main enzyme responsible for the sulphation of cholesterol. As such, SULT2B1b may play the role as a key regulator of cholesterol metabolism. Variations in the sulphating activity of SULT2B1b may affect the sulphation of cholesterol and, consequently, the related physiological events. This study was designed to evaluate the impact of the genetic polymorphisms on the sulphation of cholesterol by SULT2B1b. Ten recombinant SULT2B1b allozymes were generated, expressed, and purified. Purified SULT2B1b allozymes were shown to display differential cholesterol-sulphating activities, compared with the wild-type enzyme. Kinetic studies revealed further their distinct substrate affinity and catalytic efficiency toward cholesterol. These findings showed clearly the impact of genetic polymorphisms on the cholesterol-sulphating activity of SULT2B1b allozymes, which may underscore the differential metabolism of cholesterol in individuals with different SULT2B1b genotypes.

Sulfation of catecholamines and serotonin by SULT1A3 allozymes.

Previous studies have demonstrated the involvement of sulfoconjugation in the metabolism of catecholamines and serotonin. The current study aimed to clarify the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the enzymatic characteristics of the sulfation of dopamine, epinephrine, norepinephrine and serotonin by SULT1A3 allozymes. Following a comprehensive search of different SULT1A3 and SULT1A4 genotypes, twelve non-synonymous (missense) coding SNPs (cSNPs) of SULT1A3/SULT1A4 were identified. cDNAs encoding the corresponding SULT1A3 allozymes, packaged in pGEX-2T vector were generated by site-directed mutagenesis. SULT1A3 allozymes were expressed, and purified. Purified SULT1A3 allozymes exhibited differential sulfating activity toward catecholamines and serotonin. Kinetic analyses demonstrated differences in both substrate affinity and catalytic efficiency of the SULT1A3 allozymes. Collectively, these findings provide useful information relevant to the differential metabolism of dopamine, epinephrine, norepinephrine and serotonin through sulfoconjugation in individuals having different SULT1A3/SULT1A4 genotypes.

A reappraisal of the 6-O-desmethylnaproxen-sulfating activity of the human cytosolic sulfotransferases.

In this study, we aimed to obtain a comprehensive account of the human cytosolic sulfotransferases (SULTs) that are capable of sulfating 6-O-desmethylnaproxen (O-DMN), a major metabolite of naproxen. Of the 13 known human SULTs tested, 7 (SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C2, SULT1C4, and SULT1E1) displayed O-DMN-sulfating activity, when analyzed using an elevated substrate concentration (500 µmol·L-1) together with 14 µmol·L-1 of the sulfate donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS). At 10 µmol·L-1 O-DMN concentration, however, only SULT1A1 and SULT1A3 displayed detectable activity, with the former being nearly 2 orders of magnitude more active than the latter. A pH-dependence study indicated that SULT1A1 exhibited a broad pH optimum spanning pH 5.5-7. Kinetic parameters of the sulfation of O-DMN by SULT1A1 were determined. The production and release of sulfated O-DMN was demonstrated using cultured human HepG2 hepatoma cells and Caco-2 colon carcinoma cells. Moreover, assays using human organ specimens revealed that the O-DMN-sulfating activities present in the cytosols of liver and small intestine (at 502.5 and 497.2 pmol·min-1·(mg protein)-1, respectively) were much higher than those detected for the cytosols of lung and kidney. Taken together, these results provided relevant information concerning the sulfation of O-DMN both in vitro and in vivo.