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- ArticleMiller JC, Hollatz AJ, Schuler MA.Phytochemistry. 2021 Mar;183:112626.Divergent terpene indole alkaloid (TIA) pathways in Catharanthus roseus and Camptotheca acuminata generate vinblastine and vincristine, and camptothecin, respectively. In contrast to Catharanthus which feeds secologanin (from methylated loganin) into its species-specific late pathway, Camptotheca feeds secologanic acid (from unmethylated loganic acid) into its late pathway. Having identified putative Camptotheca secologanic acid synthases (SLASs) and cytochrome P450 reductases (CPRs) in transcriptome databases, we have demonstrated that two P450s, CYP72A564 and CYP72A565, are capable of utilizing both loganic acid and loganin to generate secologanic acid and secologanin. We have extended the previous report of these activities by CYP72A565 and CYP72A610 (Yang et al., 2019) by demonstrating that both Arabidopsis CPRs (ATR1, ATR2) couple with these CYP72A proteins in yeast microsomal assays and that purified Camptotheca CPR1 couples with them in in vitro reconstitution assays. Kinetic analyses of purified full-length Camptotheca SLASs have indicated that both process loganic acid with nearly identical catalytic rates and efficiencies as measured by their kcat and kcat/KM. In contrast, CYP72A564 processes loganin with two-fold greater efficiency than CYP72A565 correlating with the former's 3-fold greater affinity for loganin. The closely-related CYP72A730 does not bind or process either compound. Molecular modeling of these three proteins and comparisons with Catharanthus secologanin synthase (SLS) have identified key differences that likely determine their SLAS versus SLS selectivities. Our ability to reconstitute these SLAS/SLS activities provides valuable tools for further examinations of the residues involved in substrate recognition and determinations of their unusual mechanism of C-C bond scission.
- ArticleDart A, Roy D, Vlaskin V, Limqueco E, Lowe NM, Srinivasan S, Ratner DM, Bhave M, Stayton P, Kingshott P.Biomater Adv. 2022 Feb;133:112626.HIV and hepatitis B are two of the most prevalent viruses globally, and despite readily available preventive treatments unforgiving treatment regimens still exist, such as daily doses of medicine that are challenging to maintain especially in poorer countries. More advanced and longer-lasting delivery vehicles can potentially overcome this problem by reducing maintenance requirements and significantly increase access to medicine. Here, we designed a technology to control the delivery of an antiviral drug over a long timeframe via a nanofiber based delivery scaffold that is both easy to produce and use. An antiviral prodrug containing tenofovir alafenamide (TAF) was synthesized by initial conjugation to glycerol monomethacrylate followed by polymerization to form a diblock copolymer (pTAF) using reversible addition-fragmentation chain transfer (RAFT). In order to generate an efficient drug delivery system this copolymer was fabricated into an electrospun nanofiber (ESF) scaffold using blend electrospinning with poly(caprolactone) (PCL) as the carrier polymer. SEM images revealed that the pTAF-PCL ESFs were uniform with an average diameter of (787 ± 0.212 nm), while XPS analysis demonstrated that the pTAF was overrepresented at the surface of the ESFs. Additionally, the pTAF exhibited a sustained release profile over a 2 month period in human serum (HS), suggesting that these types of copolymer-based drugamers can be used in conjunction with electrospinning to produce long-lasting drug delivery systems.
- ArticleGauthier JM, Cole AB, Bagge CL.Psychiatry Res. 2019 12;282:112626.Drinking to cope is associated with suicide ideation and attempts. Event-based research shows drinking, particularly when alcohol is consumed in large quantities, increases the intensity of suicidal thoughts and immediate risk for attempt. Such findings suggest those who typically drink to cope may be especially likely to drink heavily in the hours preceding a suicide attempt. In the first examination of the association between regular use of alcohol as a coping strategy and acute alcohol consumption prior to a suicide attempt, participants included 130 patients hospitalized for a recent attempt. The number of drinks consumed in the acute period preceding the attempt, as well as past-year heavy drinking frequency, typical drinking motives, and depressive symptoms were assessed. The unique impacts of coping motives on odds of consuming any alcohol, and of using specific amounts of alcohol in the acute period, were determined through binary and multinomial logistic regressions. Results demonstrated that commonly drinking for coping motives increased the odds of heavy drinking - but not of using alcohol at low levels - during the acute period. Results held after adjusting for relevant covariates. Clinicians should assess drinking motives and prioritize prevention of drinking to cope to reduce risk of alcohol-related suicide attempts.
- ArticleZhou C, Li J, Wu X, Liu F.Exp Gerontol. 2024 Dec;198:112626.BACKGROUND/AIM: Diabetes mellitus (DM) patients are at increased risk of cognitive impairment. The precise mechanisms underlying the association between DM and cognitive impairment remain unclear. Spleen tyrosine kinase (SYK), a crucial regulator of signal transduction, has been implicated in microglial pyroptosis in experimental ischemic stroke models. The present study investigated the potential role of SYK in DM-associated cognitive impairment.
METHODS: Diabetes was induced by streptozotocin (STZ) in C57BL/6 mice, and cognitive function and cerebral injury were assessed 12 weeks later using the Morris water maze (MWM), TUNEL assay and Western blotting. In vitro, the inhibition of SYK was investigated in a mouse hippocampal neuronal cell line cultured with high glucose.
RESULTS: Compared with control mice, DM mice presented impaired spatial learning and memory. Additionally, SYK activation was linked to neuronal pyroptosis, as evidenced by increases in the number of TUNEL-positive cells and protein levels of NLRP3, ASC, procaspase-1, caspase-1, GSDMD, the GSDMD N-terminal fragment, pro-IL-1β, and IL-1β in the hippocampus of DM mice. Compared with no treatment, SYK knockdown markedly attenuated cognitive impairment and histologic and ultrastructural pathological changes in the hippocampus of DM mice. The increased expression of pyroptosis-associated proteins and the increased number of TUNEL-positive cells were also significantly reduced. In vitro, high glucose significantly activated SYK to trigger the canonical pyroptotic pathway in cultured HT22 cells. The inhibition of SYK with a small interfering RNA or specific inhibitor significantly ameliorated the neuronal pyroptosis mediated by high glucose.
CONCLUSION: Our findings demonstrate that SYK activation plays a pivotal role in promoting the cognitive impairment associated with DM. This effect is mediated by triggering neuronal pyroptosis through the canonical NLRP3/Caspase-1/GSDMD pathway. These results suggest that SYK may serve as a potential target for preventing or mitigating cognitive impairment in patients with DM. - ArticleSun B, Zhang J, Liu M, Guan L.Biomed Pharmacother. 2022 02;146:112626.
- ArticleBjörvang RD, Hallberg I, Pikki A, Berglund L, Pedrelli M, Kiviranta H, Rantakokko P, Ruokojärvi P, Lindh CH, Olovsson M, Persson S, Holte J, Sjunnesson Y, Damdimopoulou P.Environ Res. 2022 05 15;208:112626.Persistent organic pollutants (POPs) are industrial chemicals resistant to degradation and have been shown to have adverse effects on reproductive health in wildlife and humans. Although regulations have reduced their levels, they are still ubiquitously present and pose a global concern. Here, we studied a cohort of 185 women aged 21-43 years with a median of 2 years of infertility who were seeking assisted reproductive technology (ART) treatment at the Carl von Linné Clinic in Uppsala, Sweden. We analyzed the levels of 9 organochlorine pesticides (OCPs), 10 polychlorinated biphenyls (PCBs), 3 polybrominated diphenyl ethers (PBDEs), and 8 perfluoroalkyl substances (PFASs) in the blood and follicular fluid (FF) samples collected during ovum pick-up. Impact of age on chemical transfer from blood to FF was analyzed. Associations of chemicals, both individually and as a mixture, to 10 ART endpoints were investigated using linear, logistic, and weighted quantile sum regression, adjusted for age, body mass index, parity, fatty fish intake and cause of infertility. Out of the 30 chemicals, 20 were detected in more than half of the blood samples and 15 in FF. Chemical transfer from blood to FF increased with age. Chemical groups in blood crossed the blood-follicle barrier at different rates: OCPs > PCBs > PFASs. Hexachlorobenzene, an OCP, was associated with lower anti-Müllerian hormone, clinical pregnancy, and live birth. PCBs and PFASs were associated with higher antral follicle count and ovarian response as measured by ovarian sensitivity index, but also with lower embryo quality. As a mixture, similar findings were seen for the sum of PCBs and PFASs. Our results suggest that age plays a role in the chemical transfer from blood to FF and that exposure to POPs significantly associates with ART outcomes. We strongly encourage further studies to elucidate the underlying mechanisms of reproductive effects of POPs in humans.
- ArticleMarin DP, Astorino TA, Martinatto F, Ragazzini FT, Bispo RE, Foschini D, Otton R.Physiol Behav. 2019 10 15;210:112626.This study examined the perceptual responses to various upper-body sprint interval exercise (SIE) protocols matched for total work and work/rest ratio. Fourteen active men (24 ± 4 years, BMI = 26.2 ± 2.7 kg/m2, body fat = 11.5 ± 4.4%) participated in 3 all-out SIE protocols consisting of battling rope exercise: P10:30 (12 × 10-s bouts with 30-s recovery); P15:45 (8 × 15-s bouts with 45 s recovery); and P30:90 (4 × 30-s bouts with 90-s recovery). During exercise, affective valence (FS +5 to -5), arousal (FAS 1-6), rating of perceived exertion (RPE 6-20), and heart rate (HR) were assessed. Post-exercise, enjoyment, self-efficacy, and intentions were measured. Results revealed a significant decline in FS (p = .02; partial eta squared [η2p] = 0.27) and a progressive increase in FAS (p = .001; η2p = 0.86), RPE (p = .001; η2p = 0.88), and HR (p = .001; η2p = 0.94), but no protocol X time interaction. Affective valence reached a nadir at values equal to -0.36 ± 3.41 (Cohen's d = -0.49), -0.43 ± 3.75 (Cohen's d = -0.44), and - 0.93 ± 3.49 (Cohen's d = -0.56) in response to P10:30, P15:45, and P30:90, respectively. There were no differences between protocols for enjoyment, intention, or self-efficacy. A negative relationship exhibited between FS and RPE was moderated by participants' tolerance of exercise intensity (β = 1.84, p < .05). Further, the association between FS and future intention was mediated by self-efficacy. Overall, upper-body SIE protocols exhibit similar perceptual responses when volume and work to rest ratio (1:3) are matched. Tolerance of exercise intensity may be used to predict changes in FS during SIE.
- ArticleMandal A, Dutta A, Das R, Mukherjee J.Mar Pollut Bull. 2021 Sep;170:112626.Intertidal microbial communities occur as biofilms or microphytobenthos (MPB) which are sediment-attached assemblages of bacteria, protozoa, fungi, algae, diatoms embedded in extracellular polymeric substances. Despite their global occurrence, they have not been reviewed in light of their structural and functional characteristics. This paper reviews the importance of such microbial communities and their importance in carbon dioxide sequestration as well as pollutant bioremediation. Global annual benthic microalgal productivity was 500 million tons of carbon, 50% of which contributed towards the autochthonous carbon fixation in the estuaries. Primary production by MPB was 27-234 gCm-2y-1 in the estuaries of Asia, Europe and the United States. Mechanisms of heavy metal removal remain to be tested in intertidal communities. Cyanobacteria facilitate hydrocarbon degradation in intertidal biofilms and microbial mats by supporting the associated sulfate-reducing bacteria and aerobic heterotrophs. Physiological cooperation between the microorganisms in intertidal communities imparts enhanced ability to utilize polycyclic aromatic hydrocarbon pollutants by these microorganisms than mono-species communities. Future research may be focused on biochemical characteristics of intertidal mats and biofilms, pollutant-microbial interactions and ecosystem influences.
- ArticleXu Y, Jiang Z, Li H, Cai J, Jiang Y, Ortiz-Guzman J, Xu Y, Arenkiel BR, Tong Q.Cell Rep. 2023 Jun 27;42(6):112626.
- ArticlePereira ZC, Cruz JMDA, Corrêa RF, Sanches EA, Campelo PH, Bezerra JA.Food Res Int. 2023 04;166:112626.The Passiflora genus (Passifloraceae family) extends worldwide, but it is mainly found in the Americas. The present review aimed to select the main reports published over the last 5 years involving the chemical composition, health benefits, and products obtained from the pulps of Passifora spp. The pulps of at least 10 species of Passiflora have been studied presenting different classes of organic compounds, especially phenolic acids, and polyphenols. The main bioactivity properties include antioxidant and in vitro α-amylase and α-glucosidase enzyme inhibition. These reports highlight the potential of Passiflora for the development of a variety of products, especially fermented and non-fermented beverages, as well as foods to attend a demand for non-dairy products. In general, these products are prominent source of probiotic bacteria resistant to in vitro gastrointestinal simulation, representing an alternative for intestinal microbiota regulation. Therefore, sensory analysis is encouraging herein, as well as in vivo tests to enable the development of high value pharmaceuticals and food products. The patents confirm the great interest in research and products development in different food technology areas, as well as in biotechnology, pharmacy, and materials engineering.
- ArticleFranco D, Zamudio J, Blevins KM, Núñez-Larios EA, Ricoy UM, Iñiguez SD, Zavala AR.Behav Brain Res. 2020 07 01;389:112626.Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces quick and effective antidepressant results in depressed juvenile and adult individuals. The long-term consequences of using ketamine in juvenile populations are not well known, particularly as it affects vulnerability to drugs of abuse later in life, given that ketamine is also a drug of abuse. Thus, the current study examined whether early-life ketamine administration produces long-term changes in the sensitivity to the rewarding effects of ethanol, as measured using the conditioned place preference (CPP) paradigm. On postnatal day (PD) 21, juvenile male and female rats were pretreated with ketamine (0.0 or 20 mg/kg) for 10 consecutive days (i.e., PD 21-30) and then evaluated for ethanol-induced CPP (0.0, 0.125, 0.5, or 2.0 g/kg) from PD 32-39. Results revealed that early-life ketamine administration attenuated the rewarding properties of ethanol in male rats, as ketamine pretreated rats failed to exhibit ethanol-induced CPP at any dose compared to saline pretreated rats, which showed an increased preference towards the ethanol-paired compartment in a dose-dependent manner. In females, ethanol-induced CPP was generally less robust compared to males, but ketamine pretreatment resulted in a rightward shift in the dose-response curve, given that ketamine pretreated rats needed a higher dose of ethanol compared to saline pretreated rats to exhibit ethanol-induced CPP. When considered together, the findings suggest that early use of ketamine does not appear to enhance the vulnerability to ethanol later in life, but in contrast, it may attenuate the rewarding effects of ethanol.
- ArticleTimiryasova TM, Luo P, Zheng L, Singer A, Zedar R, Garg S, Petit C, Moore S, Hu BT, Brown M.J Immunol Methods. 2019 11;474:112626.The rabies rapid fluorescent focus inhibition test (RFFIT) is the most widely used cell-based assay for detecting and quantitating rabies virus neutralizing antibodies (RVNA) in human serum. However, it is a complex, labor intensive, and somewhat subjective manual assay, the performance of which may be affected by a number of factors including the quality of cells and virus, variability of assay reagents and the skill and expertise of analysts. This study sought to identify and evaluate conditions that may impact RFFIT performance and RVNA detection by evaluating assay parameters including: different serial dilution scheme of serum samples in a 96-well microplate using semi-automated pipetting systems, the range of dose of challenge virus standard (CVS-11) strain of rabies virus, the effect of complement (C'), the effect of cell seeding density and passage number, the effect of diethylaminoethyl (DEAE) dextran concentration on virus infectivity, and the assay incubation period prior to immunostaining. In addition the evaluation of counting fluorescent foci using a microscope versus using scanned images from a cell imaging reader was performed in an effort to ease the reading of slides and have permanent records of the raw data. The results from optimization of each parameter are presented along with subsequent assay validation in accordance with the International Conference on Harmonization (ICH) guidelines. The improved and optimized RFFIT accuracy, linearity and sensitivity was demonstrated by testing World Health Organization (WHO)-1 and WHO-2 Standard Rabies Immune Globulins (SRIGs) and complete assay development and validation was performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines.
- ArticleWu Q, Wang D, Chen C, Peng C, Cai D, Wu Z.J Environ Manage. 2021 Jul 15;290:112626.In this study, a magnetic nanocomposite (denoted as FZ) was fabricated using Fe3O4and zeolitic imidazolate framework-8 (ZIF-8), based on a coprecipitation method. FZ could efficiently remove Cu2+(Cu(II)) and AsO2- (As(III)) ions simultaneously from water, soil, and swine urine samples through hydrogen bonding and electrostatic interactions. The Cu(II) and As(III) removal efficiencies of the optimal FZ sample increased gradually with time and reached 99.1% and 98.4%, respectively, in 180 min. The maximum adsorption capacities of FZ4 for Cu(II) and As(III) were determined to be 33.48 mg/g and 21.12 mg/g, respectively. Additionally, the FZ with a high saturation magnetization (49.8 emu/g) was easily recovered from aqueous solutions and soil samples. Furthermore, zebrafish experiments indicated that FZ possessed a high biosafety. Thus, this study introduces a promising method for treating water, soil, and swine urine samples contaminated with Cu(II) and As(III), and verifies that FZ is suitable for practical application.
- ArticleChiu JZS, Castillo AM, Tucker IG, Radunskaya AE, McDowell A.Colloids Surf B Biointerfaces. 2022 Sep;217:112626.The interaction of nanoparticles with Caco-2 monolayers in cell culture underpins our predictions of the uptake of nanoformulations in vivo for drug delivery. Cell-penetrating peptides (CPP), such as oligoarginine, are currently of interest to enhance cellular uptake of bioactives and nanoparticles. This paper assesses the cellular association of poly(ethyl-cyanoacrylate) nanoparticles functionalized with di-arginine-histidine (RRH) in a Caco-2 cell model. We applied a computational model of particokinetics, In vitro Sedimentation, Diffusion and Dosimetry (ISDD) to predict the accumulation of nanoparticles on the cell surface. An important finding is that the proportion of nanoparticles associated with cells was less than 5 %. This has important implications for interpreting nanoparticle uptake in vitro. RRH-decoration does not appear to alter nanoparticle deposition, but increases association of nanoparticles with Caco-2 cells. Immediate deposition of nanoparticles on the cell surface was apparent and similar between formulations, but underestimated by the ISDD model. Key to understanding the nano-bio interface for drug delivery, nanoparticles that reach the cells were not necessarily absorbed by them, but can become detached. This variable of nanoparticle release from cells was incorporated into a new mathematical model presented here.
- ArticleWang N, Yang X, Jiao S, Zhang J, Ye B, Gao S.PLoS One. 2014;9(11):e112626.Antibiotic-resistant bacteria and genes are recognized as new environmental pollutants that warrant special concern. There were few reports on veterinary antibiotic-resistant bacteria and genes in China. This work systematically analyzed the prevalence and distribution of sulfonamide resistance genes in soils from the environments around poultry and livestock farms in Jiangsu Province, Southeastern China. The results showed that the animal manure application made the spread and abundance of antibiotic resistance genes (ARGs) increasingly in the soil. The frequency of sulfonamide resistance genes was sul1 > sul2 > sul3 in pig-manured soil DNA and sul2 > sul1 > sul3 in chicken-manured soil DNA. Further analysis suggested that the frequency distribution of the sul genes in the genomic DNA and plasmids of the SR isolates from manured soil was sul2 > sul1 > sul3 overall (p<0.05). The combination of sul1 and sul2 was the most frequent, and the co-existence of sul1 and sul3 was not found either in the genomic DNA or plasmids. The sample type, animal type and sampling time can influence the prevalence and distribution pattern of sulfonamide resistance genes. The present study also indicated that Bacillus, Pseudomonas and Shigella were the most prevalent sul-positive genera in the soil, suggesting a potential human health risk. The above results could be important in the evaluation of antibiotic-resistant bacteria and genes from manure as sources of agricultural soil pollution; the results also demonstrate the necessity and urgency of the regulation and supervision of veterinary antibiotics in China.
- ArticleChen L, Sun Z, Xu H, Xie Q, Qi M, Tian X, Wang T.Exp Cell Res. 2021 07 15;404(2):112626.As the most common endocrine-related malignant tumor, the prevalence of thyroid cancer (TC) has soared strikingly over the past thirty years then verged to stabilization or even descension temporally. Distributed in a cell-specific manner, circular RNAs (circRNAs) is a novel class of non-coding RNAs characterized by its covalently closed loop without 5'-terminal cap and 3'-terminal poly A tail, which guarantee its distinctive evolutionary conservation and exonucleases resistance. Emerging evidence indicates that circRNA participates in the pathogenesis and carcinogenesis of several cancers including thyroid cancer. In this review, we concentrated on the connection between circRNAs and thyroid cancer so as to obtain a more profound understanding. We aim to discuss this relationship between TC and circRNAs by summarizing the effect of various circRNAs on tumor biological behaviors and clinical application, and systematically outlook the conceivable application of circRNAs in TC diagnosis and therapy.
- ArticleAghaalikhani F, Rezazadeh A, Eini-Zinab H, Sobhani SR.Nutrition. 2024 Nov 12;131:112626.BACKGROUND & AIMS: Sustainable diets are characterized by being culturally acceptable, economically fair, affordable and accessible to all, nutritionally sufficient, safe and healthy, and are efficient in their utilization of human and other natural resources. The aim of the present study was to determine the difference in the cost and affordability of providing nutritious and sustainable food baskets in different zones of Iran 2016 through 2019.
MATERIAL & METHODS: In this repeated cross-sectional study, the expenditure and income data of 128,716 Iranian households that participated in the "Household Income and Expenditure Survey" 2016 through 2019 were used. The data were categorized into 11 zones according to the zone classification of the previous National Integrated Micronutrient Survey. The sustainable and nutritious food baskets were modeled using linear programming and ideal programming. The cost of the baskets was calculated by summing the average price of each food item based on the amount (in grams) of each item in the food basket. Affordability was estimated based on the total cost of each basket compared to the average monthly disposable income of the household. Data were analyzed using R software (version 4.3.0). One-way analysis of variance and posthoc statistical tests were used to compare the difference between the average cost and affordability of food baskets in different zones.
RESULTS: In all zones, the cost of a nutritious food basket was higher than the cost of a current food basket, and the cost of a sustainable food basket was lower than the cost of receiving the current food basket. The highest cost of current and sustainable food basket was in Zone 1 (93001.89 and 73290.27 Rials, respectively) and the lowest cost of those baskets was in Zone 10 (81484.38 and 63655.62 Rials, respectively). As for the nutritious food basket, the highest cost basket was seen in Zone 1 (116277.05 Rials), but the lowest cost one was in Zone 3 (29210.98 Rials). In terms of affordability, for all three food baskets, households in Zone 5 had the highest (74.34%, 57.49%, and 92.12%, respectively) and households in Zone 8 had the lowest (24.28%, 19.20%, and 30.00%, respectively) percentage of income spent on preparing food baskets.
CONCLUSION: The findings indicate that, overall, in all different zones of Iran, the cost of the nutritious and sustainable food basket was higher and lower than the current food basket, respectively. Regarding affordability, households in Zone 5 allocated the largest percentage of their income to preparing food baskets. These findings emphasize the importance of future planning and policy implementation focused on food support, particularly in drought-affected and deprived zones. Additionally, targeted interventions could focus on enhancing the affordability of the nutritious and sustainable food basket for vulnerable populations. - ArticleCrugeira PJL, Almeida HHS, Teixeira LG, Barreiro MF.J Photochem Photobiol B. 2023 Jan;238:112626.Antimicrobial resistance is a problem in contemporary society, with Staphylococcus aureus standing out as a threat due to its ability to colonize, its pathogenicity, and its expression of several virulence factors. In this context, antimicrobial photodynamic inactivation (aPDI) emerges as an alternative to conventional microbicidal or microbiostatic systems, enabling numerous and successive applications without developing side effects and microbial resistance. In this context, an aPDI system against cultures of S. aureus based on a water-in-oil (W/O) emulsion incorporating curcumin as the photosensitizer (PS), with and without olive leaf extract (OLE), was developed and the antibacterial efficacy evaluated under LED activation (ʎ450 ± 10 nm) by depositing an energy density of 14 J/cm2. The produced emulsified systems showed no significant differences in the droplet size and morphology, remaining stable along the tested period of 30 days. The bacterial reduction achieved after the first aPDI application for the emulsions added with curcumin and curcumin combined with the OLE was 5 log10 CFU.mL-1 and 6 log10 CFU.mL-1, respectively, revealing a significant difference between the two groups (p < 0.0001). After the second aPDI application, an increased microbial reduction (7 log10 CFU.mL-1) was observed for both studied groups even with a low significant difference (p < 0.05). The PS loading through an emulsified system for aPDI obtained a bactericidal action against S. aureus, increased by applying two aPDI, showing a significant synergy between photodynamic inactivation, OLE delivery and antibacterial activity. In addition, the developed solutions were produced using natural products by an ecologically correct process.
- ArticleWang L, Casey MC, Vernekar SKV, Sahani RL, Kankanala J, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z.Eur J Med Chem. 2020 Oct 15;204:112626.The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic stability. Therefore, there has been increasing interest in designing novel sub-chemotypes of PF74 with similar binding mode and improved metabolic stability. We report herein our efforts to explore the inter-domain interacting indole moiety for designing novel CA-targeting small molecules. Our design includes simple substitution on the indole ring, and more importantly, novel sub-chemotypes with the indole moiety replaced with a few less electron-rich rings. All 56 novel analogs were synthesized and evaluated for antiviral activity, cytotoxicity, and impact on CA hexamer stability. Selected analogs were tested for metabolic stability in liver microsomes. Molecular modeling was performed to verify compound binding to the PF74 site. In the end, 5-hydroxyindole analogs (8,9 and 12) showed improved potency (up to 20-fold) over PF74. Of the novel sub-chemotypes, α- and β-naphthyl analogs (33 and 27) exhibited sub micromolar antiviral potencies comparable to that of PF74. Interestingly, although only moderately inhibiting HIV-1 (single-digit micromolar EC50s), analogs of the 2-indolone sub-chemotype consistently lowered the melting point (Tm) of CA hexamers, some with improved metabolic stability over PF74.
- ArticleLiang Y, Yi L, Deng P, Wang L, Yue Y, Wang H, Tian L, Xie J, Chen M, Luo Y, Yu Z, Pi H, Zhou Z.Ecotoxicol Environ Saf. 2021 Aug 16;224:112626.Cadmium (Cd) is a carcinogen that stimulates breast cancer (BC) progression. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus that possesses a wide array of pharmacological activities, including anti-BC activity. However, the effects of rapamycin on Cd-increased BC progression and the underlying mechanism have not been fully elucidated. Here, we hypothesize that rapamycin antagonizes Cd-induced BC cell proliferation and metastasis by directly modulating ACSS2. In this study, we found that rapamycin efficiently inhibited Cd-induced proliferation, invasion and migration in MCF-7 and T47-D cells. Moreover, a surface plasmon resonance (SPR) assay confirmed that rapamycin directly binds to the ACSS2 protein with a calculated equilibrium dissociation constant (KD) of 18.3 μM. Molecular docking showed that there are three binding sites in the ACSS2 protein and that rapamycin binds at the coenzyme A (COA) binding site with a docking score of - 12.26 and a binding free energy of - 26.34 kcal/mol. More importantly, rapamycin suppresses Cd-induced BC progression by activating ACSS2. After cells were cotreated with an ACSS2 inhibitor, the effects of rapamycin were abolished. In conclusion, our findings suggest that rapamycin suppresses Cd-augmented BC progression by upregulating ACSS2, and ACSS2 may serve as a direct target of rapamycin for inhibiting xenobiotic (e.g., Cd)-mediated BC progression.