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2.
Pharmacol Biochem Behav ; 240: 173776, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38679080

ABSTRACT

Alcohol use disorder (AUD) affects >15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. The cannabinoid receptor type 1 (CB1) has been a target of interest for the development of medications for substance use disorders and other compulsive disorders. However, CB1 antagonists/inverse agonists (e.g., rimonabant) have severe side effects that limit their clinical utility, including anxiety, depression, and suicide. Recent development of CB1 negative allosteric modulators (NAMs), including PSNCBAM-1, may provide an alternative mechanism of attenuating CB1 signaling with reduced side effects. PSNCBAM-1 has not yet been evaluated for effects in models of AUD. In this study, we investigated the effects of the CB1 NAM, PSNCBAM-1, in rodent models of AUD using adult male mice. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration (8 % w/v ethanol in water), significantly reducing ethanol rewards at a dose of 30 mg/kg, but not at 10 or 18 mg/kg. PSNCBAM-1 also dose-dependently attenuated palatable food self-administration (diluted vanilla Ensure), significantly reducing food rewards at 18 and 30 mg/kg PSNCBAM-1. PSNCBAM-1 did not affect conditioned place preference for 2 g/kg ethanol. These results suggest PSNCBAM-1 reduces ethanol-taking behavior via a nonspecific hypophagic effect and does not reduce the rewarding effects of ethanol.


Subject(s)
Ethanol , Receptor, Cannabinoid, CB1 , Self Administration , Animals , Male , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Mice , Ethanol/administration & dosage , Ethanol/pharmacology , Allosteric Regulation/drug effects , Mice, Inbred C57BL , Alcoholism/drug therapy , Pyridines/pharmacology , Pyridines/administration & dosage , Alcohol Drinking/psychology , Phenylurea Compounds
4.
ACS Nano ; 18(2): 1647-1657, 2024 Jan 16.
Article in English | MEDLINE | ID: mdl-38166382

ABSTRACT

Lead-free low-dimensional copper-based metal halides are promising luminescent materials for broadband LEDs owing to their broad self-trapped exciton (STE) emission. However, recently, in 1D CsCu2I3, a discrepancy between their electroluminescence (EL) and photoluminescence (PL) has been observed. As a result, the overall output color from LEDs is significantly different than the anticipated emission. To unveil the origin of this discrepancy, here, we provide comprehensive analyses and show that the shift in the EL is caused neither by any structural/optical interactions between CsCu2I3 and electron transport layers (ETL) nor by the degradation of 1D CsCu2I3. Instead, it depends on the carrier imbalance on CsCu2I3, mainly due to the difference in the electron mobility of the ETLs and the electron density on the CsCu2I3 layer. By varying the ETLs, different colored 1D CsCu2I3 LEDs with peaks at 556, 590, and 647 nm are fabricated, and a maximum luminance of over 2000 cd/m2 is achieved for a 556 nm LED. Further, by limiting the electron mobility and injection to 1D CsCu2I3 using an insulating LiF layer at the CsCu2I3/ETL interface, more red-shifted LEDs are achieved confirming the critical role of electron density on the EL characteristics of 1D CsCu2I3.

5.
ACS Nano ; 17(17): 17233-17244, 2023 09 12.
Article in English | MEDLINE | ID: mdl-37639711

ABSTRACT

For certain nanotechnological applications of the contractile proteins actin and myosin, e.g., in biosensing and network-based biocomputation, it would be desirable to temporarily switch on/off motile function in parts of nanostructured devices, e.g., for sorting or programming. Myosin XI motor constructs, engineered with a light-switchable domain for switching actin motility between high and low velocities (light-sensitive motors (LSMs) below), are promising in this regard. However, they were not designed for use in nanotechnology, where longevity of operation, long shelf life, and selectivity of function in specific regions of a nanofabricated network are important. Here, we tested if these criteria can be fulfilled using existing LSM constructs or if additional developments will be required. We demonstrated extended shelf life as well as longevity of the actin-propelling function compared to those in previous studies. We also evaluated several approaches for selective immobilization with a maintained actin propelling function in dedicated nanochannels only. Whereas selectivity was feasible using certain nanopatterning combinations, the reproducibility was not satisfactory. In summary, the study demonstrates the feasibility of using engineered light-controlled myosin XI motors for myosin-driven actin transport in nanotechnological applications. Before use for, e.g., sorting or programming, additional work is however needed to achieve reproducibility of the nanofabrication and, further, optimize the motor properties.


Subject(s)
Actins , Nanostructures , Myosins , Nanotechnology , Cell Movement
6.
J Environ Manage ; 345: 118703, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37540983

ABSTRACT

Forestry has long been considered an effective means of restoring degraded drylands worldwide. Often, afforestation in such lands relies on the establishment of runoff harvesting systems that are formed as contour bench terraces on hillslopes, increasing water availability for the planted trees and shrubs. The construction of terraces requires intensive earthworks by heavy machinery. This study assessed the long-term (>10 yrs) effects of forestry-related land-use change on soil properties and herbaceous vegetation in 16-year-old and 12-year-old afforestation sites (established in 2005 and 2009), and in nearby control ("natural") areas in the semi-arid northern Negev, Israel. Mean herbaceous vegetation height in the 2005 afforestation sites (12.1 cm) was significantly (P = 0.0009) and 23% greater than in the control areas (9.8 cm), whereas in the 2009 afforestation sites (6.2 cm) it was 37% lesser than in the control areas. Mean herbaceous vegetation aboveground biomass was similar in the 2005 afforestation (0.39 Mg ha-1) and control areas (0.38 Mg ha-1), and almost significantly (P = 0.0510) and twofold greater than in the 2009 afforestation sites (0.19 Mg ha-1). The effect of hillslope aspect on these variables was substantial; their mean values were higher in the northern (mesic) hillslopes than in the southern (xeric) hillslopes. Soil samples were obtained from depths of 0-5 and 5-10 cm and physio-chemo-biological properties were assessed in the laboratory. The overall soil quality - as calculated by two soil quality indices (SQIs), including the generalized SQI (SQIgen) and the minimum dataset SQI (SQIMDS) - was significantly (P < 0.0001 for both indices) and 13-22% greater in the control areas (0.52 and 0.61, respectively) than that in the afforestation treatments (0.44-0.46 and 0.50-0.51, respectively). These results are generally attributed to the removal of soil's A-horizon during earthworks, and the exposure of the underlying B-horizon. The similar SQI values of both hillslope aspects, as well as of both soil depths, indicate the generally degraded state of the entire region. In conclusion, while contour bench terracing may facilitate the recovery of herbacaeous vegetation to some extent, the effectiveness of this practice for soil restoration is questionable. Overall, insights of this study demonstrate a caveat that converting natural drylands to forestry systems may not yield sufficient ecological benefits, and therefore should be implemented with caution.


Subject(s)
Carbon , Soil , Carbon/analysis , Trees/metabolism , Forestry , Plants/metabolism , China , Ecosystem
7.
Plants (Basel) ; 12(6)2023 Mar 20.
Article in English | MEDLINE | ID: mdl-36987073

ABSTRACT

Faced with the environmental challenges posed by climate change, architects are creating nature-based solutions for urban areas, such as transforming living trees into artificial architectural structures. In this study, we have analyzed stem pairs of five tree species conjoined for more than eight years by measuring the stem diameters below and above the resulting inosculation and by calculating the respective diameter ratio. Our statistical analyses reveal that Platanus × hispanica and Salix alba stems do not differ significantly in diameter below inosculation. However, in contrast to P. × hispanica, the diameters of the conjoined stems above inosculation differ significantly in S. alba. We provide a binary decision tree based on diameter comparisons above and below inosculation as a straightforward tool for identifying the likelihood of full inosculation with water exchange. Moreover, we have compared branch junctions and inosculations by means of anatomical analyses, micro-computed tomography, and 3D reconstructions showing similarities in the formation of common annual rings that increase the capacity for water exchange. Due to the highly irregular cell arrangement in the center of the inosculations, cells cannot be assigned clearly to either of the stems. In contrast, cells in the center of branch junctions can always be attributed to one of the branches.

8.
Sci Rep ; 13(1): 1451, 2023 01 26.
Article in English | MEDLINE | ID: mdl-36702865

ABSTRACT

Large-scale urban growth has modified the hydrological cycle of our cities, causing greater and faster runoff. Urban forests (UF), i.e. the stock of trees and shrubs, can substantially reduce runoff; still, how climate, tree functional types influence rainfall partitioning into uptake and runoff is mostly unknown. We analyzed 92 published studies to investigate: interception (I), transpiration (T), soil infiltration (IR) and the subsequent reduction in runoff. Trees showed the best runoff protection compared to other land uses. Within functional types, conifers provided better protection on an annual scale through higher I and T but broadleaved species provided better IR. Regarding tree traits, leaf area index (LAI) showed a positive influence for both I and T. For every unit of LAI increment, additional 5% rainfall partition through T (3%) and I (2%) can be predicted. Overall, runoff was significantly lower under mixed species stands. Increase of conifer stock to 30% in climate zones with significant winter precipitation and to 20% in areas of no dry season can reduce runoff to an additional 4%. The study presented an overview of UF potential to partition rainfall, which might help to select species and land uses in different climate zones for better storm-water management.


Subject(s)
Tracheophyta , Water , Forests , Rain , Trees , Water Cycle , Water Movements , Water Supply
9.
PLoS One ; 17(8): e0263205, 2022.
Article in English | MEDLINE | ID: mdl-35947542

ABSTRACT

Soil organic carbon (SOC) plays a key role in regulating soil quality functions and ecosystem services. The objective of our study was to evaluate the impact of deforestation and subsequent land-use change on the SOC and total nitrogen (TN) concentration, quality, and lability under otherwise similar soil and environmental conditions. Geo-referenced composite soils (0 to 30 cm depth at 7.5 cm interval) sampled from agriculture, bioenergy plantations (Miscanthus x giganteus), Conservation Reserve Program (CRP), and wetland were analyzed for SOC, TN, active C (AC), humic- and fulvic acid (HA and FA), non-humic C (NH), E4: E6 ratio, humification indices (HI, HR, and DH), and carbon and nitrogen management indices (CPI, NPI, and CMI), compared to soils under protected forest as a control. Results showed that the CRP had the highest depth distribution and profile-wise stocks of SOC, TN, AC, and FA with respect to the lowest in agriculture upon conversion of forest. Moreover, the SOC and TN contents were significantly stratified in the CRP when compared to agriculture. While agriculture had the wider HA: FA ratios with highest HI and HR but lowest DH values, the CRP, in contrast, had the narrow HA: FA ratios with lowest HI but highest DH values, when compared to the forest. Spectral analyses have shown lower E4: E6 ratios under the forest when compared to both agriculture and the CRP; however, the later had significantly higher E4: E6 ratios than that of agriculture. The CPI, as measures of SOC accumulation or depletion, significantly decreased by 16% under agriculture but increased by 12% under the CRP. While the CMI, as measures of SOC accumulation or depletion and lability, with higher values under the CRP suggested a proportionally more labile SOC accumulation, in contrast, the smaller values under agriculture indicated a greater depletion of labile SOC over time. Moreover, the CRP may have favored a more labile SOC accumulation with higher proportions of aliphatic C compounds, whereas agriculture may have a SOC with high proportions of non-labile aromatic C compounds. Principal components analysis clearly separated and/or discriminated the land-use impacts on soil carbon pools and TN. Likewise, redundancy analysis of the relationship between measured soil parameters and land-use validated that the TOC, TN, FA, humin, and CPI were significantly impacted due to synergism among soil properties as positively influenced by the CRP upon conversion of agriculture.


Subject(s)
Carbon , Soil , Agriculture/methods , Carbon/analysis , China , Conservation of Natural Resources , Ecosystem , Nitrogen/analysis
10.
Respir Med Case Rep ; 37: 101640, 2022.
Article in English | MEDLINE | ID: mdl-35345568

ABSTRACT

Inhalational injury to the upper and lower airway occurs due to thermal or chemical irritation causing airway edema, capillary leak, mucin, and fibrin debris forming clots and soot. The use of unfractionated heparin (UFH) nebulization was found to be effective by dissolving airway clots. We report a case of inhalational burn injury where UFH nebulization led to a better outcome. A healthy male was trapped in a residential room during a fire in the building. He sustained facial, neck, upper chest, and left upper extremity burns accounting for 25% of body surface area. He was intubated at the site and started on supportive care. In the surgical intensive care unit, bronchoscopy showed severe tracheobronchial burn injury; a thorough lavage was done, started on UFH and N-acetylcysteine nebulization (NAC). The patient improved, and his trachea was extubated on day 6. In our patient, unfractionated heparin nebulization was beneficial as the patient was extubated early without landing to acute respiratory distress syndrome.

11.
Nucleic Acids Res ; 50(2): 731-749, 2022 01 25.
Article in English | MEDLINE | ID: mdl-35018432

ABSTRACT

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5' splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and other minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.


Subject(s)
Introns , RNA Precursors/genetics , RNA Splicing , Regulatory Sequences, Ribonucleic Acid , Alternative Splicing , Base Composition , Base Sequence , Computational Biology/methods , Exons , Gene Library , HEK293 Cells , Humans , Nucleotide Motifs , Position-Specific Scoring Matrices , RNA Splice Sites , Sequence Analysis, RNA , Survival of Motor Neuron 2 Protein/genetics
12.
Sci Rep ; 12(1): 671, 2022 01 13.
Article in English | MEDLINE | ID: mdl-35027622

ABSTRACT

Green infrastructure (GI) has emerged as a feasible strategy for promoting adaptive capacities of cities to climate change by alleviating urban heat island (UHI) and thus heat stress for humans. However, GI can also intensify the winter cold stress. To understand the extent of UHI within a city as well as the link between outdoor thermal stress both diurnally and seasonally, we carried out an empirical study in Würzburg, Germany from 2018 to 2020. At sub-urban sites, relative humidity and wind speed (WS) was considerably higher and air temperature (AT) lower compared to the inner city sites. Mean AT of inner city sites were higher by 1.3 °C during summer and 5 °C during winter compared to sub-urban sites. The magnitude followed the spatial land use patterns, in particular the amount of buildings. Consequently, out of 97 hot days (AT > 30 °C) in 3 years, 9 days above the extreme threshold of wet bulb globe temperature of 35 °C were recorded at a centre location compared to none at a sub-urban site. Extreme heat stress could be halved with 30-40% cover of greenspaces including grass lawns, green roofs, and green walls with little compromise in increasing winter cold stress.

13.
Vet Med Sci ; 7(5): 1564-1568, 2021 09.
Article in English | MEDLINE | ID: mdl-33932958

ABSTRACT

BACKGROUND: The incidence of dystocia in cats is relatively low compared to that in other pet and farm animals. However, when dystocia occurs in cats, manual, medicinal or surgical intervention is required. OBJECTIVES: Here, we report a caesarean section (C-section) in a Bangladeshi domestic cat that suffered from dystocia due to partial primary uterine inertia. METHODS: A Bangladeshi domestic queen cat was presented to the Veterinary Teaching Hospital (VTH) with signs of dystocia. The queen had given birth to one kitten 36 hr earlier; however, newborn died 30 min after birth. She was unable to deliver the remaining fetuses. The cat had gone off feed, appeared depressed, had a severely enlarged abdomen and showed no straining efforts. On palpation, bony-like structures were felt in both sides of the abdomen. Ultrasonographic (USG) examination was carried out, which confirmed the presence of two fetuses, one fetus in each uterine horn. No fetal movements could be detected. The cat was diagnosed with dystocia due to partial primary uterine inertia. RESULTS: A C-section was performed, and two emphysematous, putrefied and large dead kittens were removed. The uterus was found to be severely decomposed and foul smelling; therefore, an ovariohysterectomy was carried out to prevent development of maternal toxaemia and septicaemia. The queen recovered fully. CONCLUSION: To the best of our knowledge, we report here, for the first time, a successful C-section followed by an ovariohysterectomy in a Bangladeshi domestic cat, suffering from severe dystocia due to partial primary uterine inertia for >36 hr.


Subject(s)
Cat Diseases , Dystocia , Uterine Inertia , Animals , Cat Diseases/epidemiology , Cat Diseases/surgery , Cats , Cesarean Section/veterinary , Dystocia/epidemiology , Dystocia/surgery , Dystocia/veterinary , Female , Hospitals, Animal , Hospitals, Teaching , Pregnancy , Uterine Inertia/veterinary
14.
iScience ; 24(2): 102047, 2021 Feb 19.
Article in English | MEDLINE | ID: mdl-33554060

ABSTRACT

The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α4ß7 integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a ß sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the ß sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.

15.
Psychopharmacology (Berl) ; 238(6): 1585-1592, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33585961

ABSTRACT

RATIONALE: Opioid and GABAA receptors are both located in central nociceptive pathways, and compounds that activate these receptors have pain-relieving properties. To date, the interactive effects of concurrent administration of these compounds in preclinical models of pain-like behaviors have not been assessed. OBJECTIVE: The purpose of this study was to examine the interactive effects of the µ-opioid agonist morphine and the α2GABAA and α3GABAA receptor positive allosteric modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024) in preclinical models of mechanical hyperalgesia and thermal nociception. METHODS: The antihyperalgesic and antinociceptive effects of morphine and MP-III-024 administered alone were assessed initially, followed by fixed-ratio mixtures of MP-III-024/morphine combinations. Drug interaction data were analyzed using isobolographic and dose-addition analyses. All studies were conducted in male CD-1 mice. RESULTS: In the assay of mechanical hyperalgesia, each compound produced dose-dependent antihyperalgesic effects, whereas only morphine was effective on thermal nociception. Fixed-ratio mixtures of MP-III-024/morphine were also dose-dependently effective in both procedures. These drug combination studies revealed that morphine and MP-III-024 produced supra-additive (synergistic) effects in both assays, depending on their relative proportions. CONCLUSIONS: These results demonstrate an interaction between α2GABAA and α3GABAA receptor- and µ-opioid receptor-mediated signals and suggest that combination therapy may be useful for the treatment of pain-related disorders.


Subject(s)
Analgesics, Opioid/pharmacology , Morphine/pharmacology , Pain/drug therapy , Animals , Dose-Response Relationship, Drug , Drug Interactions , Drug Synergism , Hyperalgesia/drug therapy , Male , Mice , Receptors, GABA-A/drug effects , Receptors, Opioid, mu/agonists
16.
Cureus ; 13(12): e20627, 2021 Dec.
Article in English | MEDLINE | ID: mdl-35103197

ABSTRACT

Background The coronavirus disease 2019 (COVID-19) pandemic has manifested into an unprecedented public health crisis. The rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has facilitated reagent developers to customize and receive authorization for nucleic acid testing kits in a short period, which would have resulted in some shortcomings in the quality parameters of the kits. Consequently, in-house clinical validations of innovative real-time quantitative polymerase chain reaction (RT-qPCR) kits are required. This research aims to determine the sensitivity, specificity, and accuracy of various RT-qPCR kits available in Bangladesh. Methodology A total of 150 samples were obtained from patients with suspected COVID-19 infection when the delta variant was predominant, followed by RNA extraction performed using a nucleic acid isolation kit. Subsequently, three commercially available PCR kits named Sansure (China), STAT-NATⒷ (Sentinel Diagnostics, Italy), and Roche Biochem (Switzerland) were applied to detect SARS-CoV-2. Results The results showed that the STAT-NATⒷ kit is more sensitive than the other two, as indicated by the cycle threshold (Ct) values of respective genes. STAT-NATⒷ RT-qPCR can detect the ORF1ab gene sensitively (p < 0.001) compared to Sansure. STAT-NATⒷ was also capable of detecting E and RdRp genes more sensitively (p < 0.001) compared to Roche. Regarding specificity, STAT-NATⒷ (95% confidence interval [Cl] = 92.29-99.73%). RT-qPCR showed more accuracy than Sansure (95% Cl = 90.77-99.32%) and Roche (95% Cl = 81.17-94.38%). The area under the curve for E, ORF1ab, and RdRp genes of the STAT NATⒷ PCR kit was 0.952, 0.959, and 0.981, respectively. Conclusions This study concluded that STAT-NATⒷ is a better diagnostic RT-qPCR kit compared to Sansure and Roche for detecting SARS-CoV-2.

17.
Int J Biometeorol ; 65(2): 277-289, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33070207

ABSTRACT

Extremely high temperatures, which negatively affect the human health and plant performances, are becoming more frequent in cities. Urban green infrastructure, particularly trees, can mitigate this issue through cooling due to transpiration, and shading. Temperature regulation by trees depends on feedbacks among the climate, water supply, and plant physiology. However, in contrast to forest or general ecosystem models, most current urban tree models still lack basic processes, such as the consideration of soil water limitation, or have not been evaluated sufficiently. In this study, we present a new model that couples the soil water balance with energy calculations to assess the physiological responses and microclimate effects of a common urban street-tree species (Tilia cordata Mill.) on temperature regulation. We contrast two urban sites in Munich, Germany, with different degree of surface sealing at which microclimate and transpiration had been measured. Simulations indicate that differences in wind speed and soil water supply can be made responsible for the differences in transpiration. Nevertheless, the calculation of the overall energy balance showed that the shading effect, which depends on the leaf area index and canopy cover, contributes the most to the temperature reduction at midday. Finally, we demonstrate that the consideration of soil water availability for stomatal conductance has realistic impacts on the calculation of gaseous pollutant uptake (e.g., ozone). In conclusion, the presented model has demonstrated its ability to quantify two major ecosystem services (temperature mitigation and air pollution removal) consistently in dependence on meteorological and site conditions.


Subject(s)
Ecosystem , Microclimate , Cities , Forests , Germany , Humans , Plant Transpiration , Water
18.
Sci Rep ; 10(1): 3835, 2020 03 02.
Article in English | MEDLINE | ID: mdl-32123217

ABSTRACT

The use of antiretroviral therapy (ART) has remarkably decreased the morbidity associated with HIV-1 infection, however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. The blood-brain barrier (BBB) is the major impediment for penetration of antiretroviral drugs, causing therapeutics to reach only suboptimal level to the brain. Conventional antiretroviral drug regimens are not sufficient to improve the treatment outcomes of HAND. In our recent report, we have developed a poloxamer-PLGA nanoformulation loaded with elvitegravir (EVG), a commonly used antiretroviral drug. The nanoformulated EVG is capable of elevating intracellular drug uptake and simultaneously enhance viral suppression in HIV-1-infected macrophages. In this work, we identified the clinical parameters including stability, biocompatibility, protein corona, cellular internalization pathway of EVG nanoformulation for its potential clinical translation. We further assessed the ability of this EVG nanoformulation to cross the in vitro BBB model and suppress the HIV-1 in macrophage cells. Compared with EVG native drug, our EVG nanoformulation demonstrated an improved BBB model penetration cross the in vitro BBB model and an enhanced HIV-1 suppression in HIV-1-infected human monocyte-derived macrophages after crossing the BBB model without altering the BBB model integrity. Overall, this is an innovative and optimized treatment strategy that has a potential for therapeutic interventions in reducing HAND.


Subject(s)
Blood-Brain Barrier/metabolism , Drug Compounding , HIV-1/drug effects , Macrophages/virology , Nanoparticles/chemistry , Quinolones/chemistry , Quinolones/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Cell Line , Dose-Response Relationship, Drug , Drug Carriers/chemistry , Humans , Materials Testing , Particle Size , Poloxamer/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Quinolones/metabolism
19.
J Neuroimmune Pharmacol ; 15(3): 409-421, 2020 09.
Article in English | MEDLINE | ID: mdl-30955131

ABSTRACT

Though alcoholic liver injury plays the primary role in direct alcohol-related morbidity, alcohol consumption is also interlinked with many other diseases in extra-hepatic tissues/organs. The mechanism of alcoholic tissue injury is well documented, however the mechanisms that affect extra-hepatic tissues have not yet been well defined. Extracellular vesicles (EVs) such as exosomes and microvesicles, have been identified as key components of alcohol-induced extra-hepatic effects. We have reviewed the recent findings on the potential impact of alcohol-modified EVs/exosomes production and their downstream effects on extra-hepatic tissues. In this review, we discuss the available information on the cross-talk between hepatocytes and immune cells via EV/exosomal cargos (miRNA, mRNA, protein, etc.) in alcoholic liver diseases. We also discuss the effects of alcohol exposure on the contents of EVs/exosomes derived from various extra-hepatic tissues and their associated pathological consequences on recipient cells. Finally, we speculate on other potential EV/exosomal agents that may mediate alcohol-induced tissue damage. Graphical Abstract Alcohol can alter contents of extracellular vesicles (EVs) (e.g. exosomes) such as miRNAs, protein, cytokines, etc. in hepatic and extra-hepatic cells. The transfer of these alcohol modified EVs to nearby or distant cells can play vital role in inflammatory pathways in alcohol induced pathogenesis/comorbidities.


Subject(s)
Alcohol-Induced Disorders/pathology , Extracellular Vesicles/pathology , Alcohol-Induced Disorders/metabolism , Animals , Exosomes/pathology , Extracellular Vesicles/metabolism , Humans , Immunity, Cellular , Liver/metabolism
20.
Nano Lett ; 19(10): 7155-7163, 2019 10 09.
Article in English | MEDLINE | ID: mdl-31512480

ABSTRACT

The guided gliding of cytoskeletal filaments, driven by biomolecular motors on nano/microstructured chips, enables novel applications in biosensing and biocomputation. However, expensive and time-consuming chip production hampers the developments. It is therefore important to establish protocols to regenerate the chips, preferably without the need to dismantle the assembled microfluidic devices which contain the structured chips. We here describe a novel method toward this end. Specifically, we use the small, nonselective proteolytic enzyme, proteinase K to cleave all surface-adsorbed proteins, including myosin and kinesin motors. Subsequently, we apply a detergent (5% SDS or 0.05% Triton X100) to remove the protein remnants. After this procedure, fresh motor proteins and filaments can be added for new experiments. Both, silanized glass surfaces for actin-myosin motility and pure glass surfaces for microtubule-kinesin motility were repeatedly regenerated using this approach. Moreover, we demonstrate the applicability of the method for the regeneration of nano/microstructured silicon-based chips with selectively functionalized areas for supporting or suppressing gliding motility for both motor systems. The results substantiate the versatility and a promising broad use of the method for regenerating a wide range of protein-based nano/microdevices.


Subject(s)
Biosensing Techniques/instrumentation , Kinesins/chemistry , Myosins/chemistry , Nanostructures/chemistry , Adsorption , Animals , Cytoskeleton/chemistry , Endopeptidase K/chemistry , Equipment Design , Immobilized Proteins/chemistry , Octoxynol/chemistry , Rabbits , Surface Properties
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