LitCovid-sentences  

PMC:7463108 / 53333-72854 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T742 0-67 Sentence denotes Neural Systems Selectively Disrupted by Opiate and HIV Interactions
T743 69-115 Sentence denotes Blood-Brain Barrier and the Neurovascular Unit
T744 116-291 Sentence denotes Despite growing evidence on how opiates and HIV interact to impact the neuropathology of HIV, little is known about their interactive effects on the blood-brain barrier (BBB).
T745 292-454 Sentence denotes BBB integrity and function are critical for maintaining CNS homeostasis, and mediating neuroimmune interactions with the periphery and drug delivery into the CNS.
T746 455-565 Sentence denotes HIV and many individual HIV proteins can breakdown the BBB disrupting tight junction proteins (Dallasta et al.
T747 566-584 Sentence denotes 1999; Boven et al.
T748 585-604 Sentence denotes 2000; Andras et al.
T749 605-625 Sentence denotes 2003; Mahajan et al.
T750 626-647 Sentence denotes 2008; Banerjee et al.
T751 648-667 Sentence denotes 2010; Gandhi et al.
T752 668-683 Sentence denotes 2010; Xu et al.
T753 684-702 Sentence denotes 2012; Patel et al.
T754 703-828 Sentence denotes 2017) and decreasing transendothelial electrical resistance (TEER) (an in vitro measure of barrier integrity) (Mahajan et al.
T755 829-848 Sentence denotes 2008; Gandhi et al.
T756 849-890 Sentence denotes 2010; Mishra and Singh 2014; Patel et al.
T757 891-1018 Sentence denotes 2017), with resultant paracellular “leakage” of compounds/current between compromised barrier endothelial cells (Mahajan et al.
T758 1019-1038 Sentence denotes 2008; Gandhi et al.
T759 1039-1055 Sentence denotes 2010; Wen et al.
T760 1056-1075 Sentence denotes 2011; McLane et al.
T761 1076-1097 Sentence denotes 2014; Leibrand et al.
T762 1098-1110 Sentence denotes 2017, 2019).
T763 1111-1246 Sentence denotes Although opioids can also impair the BBB through alterations in tight junction proteins and/or increased paracellular flux (Baba et al.
T764 1247-1267 Sentence denotes 1988; Mahajan et al.
T765 1268-1284 Sentence denotes 2008; Wen et al.
T766 1285-1306 Sentence denotes 2011; Leibrand et al.
T767 1307-1467 Sentence denotes 2019), others have found that it is morphine withdrawal, not the continued exposure to morphine, that most greatly disrupts BBB integrity (Sharma and Ali 2006).
T768 1468-1627 Sentence denotes In addition to perturbing paracellular dynamics, morphine may also alter the expression and/or function of drug efflux proteins, such as P-glycoprotein (P-gp).
T769 1628-1743 Sentence denotes Sub-chronic and chronic morphine exposure is reported to increase P-gp expression and/or function (Aquilante et al.
T770 1744-1764 Sentence denotes 2000; Mahajan et al.
T771 1765-1784 Sentence denotes 2008; Yousif et al.
T772 1785-1806 Sentence denotes 2008; Leibrand et al.
T773 1807-1813 Sentence denotes 2019).
T774 1814-1911 Sentence denotes Alternatively, other investigators report no changes in P-gp with chronic exposure (Chaves et al.
T775 1912-1983 Sentence denotes 2016), while some see increases upon morphine withdrawal (Yousif et al.
T776 1984-2003 Sentence denotes 2012; Chaves et al.
T777 2004-2010 Sentence denotes 2016).
T778 2011-2148 Sentence denotes Alterations in drug transport proteins would impact the central accumulation and efficacy of therapeutic drugs that are their substrates.
T779 2149-2491 Sentence denotes Using a primary human brain microvascular endothelial cell (BMEC) and astrocyte co-culture model, Mahajan et al. (2008) were among the first to demonstrate that co-exposure to morphine and HIV-1 Tat resulted in greater increases in TNF-α and IL-8 levels and decreases in barrier tightness (measured by TEER) than either morphine or Tat alone.
T780 2492-2732 Sentence denotes Morphine and Tat co-exposure also additively increased JAM-2, while zonula occludens-1 (ZO-1) levels were decreased by morphine or by Tat individually, and occludin protein levels were decreased by morphine alone but not Tat (Mahajan et al.
T781 2733-2739 Sentence denotes 2008).
T782 2740-2901 Sentence denotes Using the inducible Tat transgenic mouse model, Leibrand et al. (2019), also demonstrated that HIV-1 Tat and morphine act independently to disrupt BBB integrity.
T783 2902-3075 Sentence denotes In these studies, morphine, and to a lesser extent Tat, exposure increased the leakage of fluorescently labeled dextrans from the circulation into the brain (Leibrand et al.
T784 3076-3097 Sentence denotes 2017, 2019) (Fig. 3).
T785 3098-3215 Sentence denotes Morphine exposure decreased the penetration of select ARVs in the brain, in a region-specific manner (Leibrand et al.
T786 3216-3231 Sentence denotes 2019) (Fig. 3).
T787 3232-3435 Sentence denotes Morphine exposure also resulted in increased expression and function of the drug efflux transport protein, P-gp, suggesting a mechanism by which morphine decreased the ARV concentrations (Leibrand et al.
T788 3436-3442 Sentence denotes 2019).
T789 3443-3589 Sentence denotes This finding suggests that morphine exposure could impact the efficient delivery of any therapeutic drug that is a substrate of P-gp into the CNS.
T790 3590-3721 Sentence denotes Future research should also investigate morphine’s impact on other drug transport proteins important for ARV delivery to the brain.
T791 3722-3823 Sentence denotes Fig. 3 Effects of HIV-1 Tat and morphine on BBB leakiness and on antiretroviral brain concentrations.
T792 3824-4114 Sentence denotes After 14 days of Tat induction, there was a significant increase in the 10 kDa (Cascade Blue®) tracer leakage into the brain in Tat + placebo as compared to Tat − placebo mice (*p < 0.05) and in Tat − mouse brains upon exposure to morphine as compared to Tat − placebo mice (*p < 0.05) (a).
T793 4115-4463 Sentence denotes There was a significant main effect of morphine, resulting in reduced integrity of the BBB and increased leakage of the higher molecular weight (40 kDa and 70 kDa) tracers in morphine-exposed groups as compared to the those groups (Tat + and Tat − together) not exposed to morphine (placebo) (#p < 0.05; significant main effect of morphine) (b, c).
T794 4464-4623 Sentence denotes Data represent the fold change in mean fluorescence intensity ± SEM; n = 8 Tat−/placebo, n = 6 Tat+/placebo, n = 9 Tat−/morphine, and n = 7 Tat+/morphine mice.
T795 4624-4799 Sentence denotes Additionally, morphine exposure increased horseradish peroxidase (HRP) extravasation from the vasculature into the perivascular space and/or parenchyma in the striatum (d, e).
T796 4800-5037 Sentence denotes HRP antigenicity was detected by indirect immunofluorescence (red) in tissue sections counterstained with Hoechst 33342 (blue) to reveal cell nuclei and visualized by differential interference contrast (DIC)-enhanced confocal microscopy.
T797 5038-5199 Sentence denotes HRP extravasation into the striatal perivascular space/parenchyma was especially prevalent in morphine-exposed mice (arrowheads; left-hand panels in e versus d).
T798 5200-5470 Sentence denotes The dotted lines (············) indicate the approximate edge of the capillaries/post-capillary venules; while intermittent dotted lines (· · · · · · ·) indicate the approximate edge of a partly sectioned blood vessel that appears partially outside the plane of section.
T799 5471-5538 Sentence denotes The asterisks (*) indicate white matter tracts within the striatum.
T800 5539-5590 Sentence denotes Representative samples from ≥ n = 4 mice per group.
T801 5591-5629 Sentence denotes All images are the same magnification.
T802 5630-5648 Sentence denotes Scale bar = 10 μm.
T803 5649-5706 Sentence denotes Antiretroviral tissue-to-plasma ratios in striatum (f–g).
T804 5707-5925 Sentence denotes Irrespective of Tat exposure, morphine significantly reduced the levels of dolutegravir (f) and abacavir (g), but not lamivudine (h), within the striatum, as compared to placebo. (* p < 0.05; main effect for morphine).
T805 5926-6151 Sentence denotes Data represent the tissue-to-plasma ratios ± SEM sampled from n = 9 Tat−/placebo, n = 9 Tat+/placebo, n = 6 Tat−/morphine, and n = 8 Tat+/morphine mice. (a–h) Modified and reprinted with permission from Leibrand et al. (2019)
T806 6152-6314 Sentence denotes HIV, HIV-1 viral proteins, and opiate-induced barrier dysfunction is associated with increased infiltration of monocyte-derived macrophages (MDMs) into the brain.
T807 6315-6461 Sentence denotes Enhanced influx of peripheral (infected) macrophages into the brain can serve to replenish viral reservoirs and further promote neuroinflammation.
T808 6462-6600 Sentence denotes Several studies have examined the individual impact of HIV, Tat, or morphine on monocyte adhesion or migration into the CNS (Nottet et al.
T809 6601-6616 Sentence denotes 1996; Wu et al.
T810 6617-6643 Sentence denotes 2000; Fischer-Smith et al.
T811 6644-6662 Sentence denotes 2001; Pello et al.
T812 6663-6684 Sentence denotes 2006; Williams et al.
T813 6685-6712 Sentence denotes 2013a, 2014; Strazza et al.
T814 6713-6734 Sentence denotes 2016; Leibrand et al.
T815 6735-6756 Sentence denotes 2017; Chilunda et al.
T816 6757-6763 Sentence denotes 2019).
T817 6764-6845 Sentence denotes However, fewer studies have examined the combined effects of HIV/Tat and opiates.
T818 6846-7004 Sentence denotes Co-exposure of HIV-1 Tat and morphine on astrocytes increases the production of chemoattractants, primarily CCL2 and CCL5, and increases microglial migration.
T819 7005-7065 Sentence denotes These effects were inhibited by MOR blockade (El-Hage et al.
T820 7066-7073 Sentence denotes 2006b).
T821 7074-7228 Sentence denotes Co-exposure of Tat and morphine or buprenorphine to a BBB model increases monocyte transmigration in response to CCL5 and other chemokines (Mahajan et al.
T822 7229-7262 Sentence denotes 2008; Jaureguiberry-Bravo et. al.
T823 7263-7269 Sentence denotes 2016).
T824 7270-7443 Sentence denotes In S. pneumoniae-infected mice, morphine and/or Tat exposure significantly enhances immune cell trafficking into the brain via actions at TLR2 and TLR4 (Dutta and Roy 2015).
T825 7444-7540 Sentence denotes Taken together, BBB damage from HIV and/or opiates can disrupt the homeostasis within the brain.
T826 7541-7868 Sentence denotes Breakdown of paracellular processes, through decreases in tight junction proteins and increased cellular adhesion proteins, increased leakage of circulating molecules into the brain and increased monocyte/MDM adhesion and transmigration into the brain, which if infected, can serve to replenish viral reservoirs within the CNS.
T827 7869-7998 Sentence denotes Furthermore, alterations in drug transport proteins within the brain can decrease ARV efficacy by decreasing drug concentrations.
T828 7999-8105 Sentence denotes Collectively, these changes serve to maintain HIV infection within the brain (see Fig. 4; Tables 1 and 2).
T829 8106-8212 Sentence denotes Fig. 4 Schematic representation of the blood-brain barrier and other components of the neurovascular unit.
T830 8213-8424 Sentence denotes Under normal conditions (represented above the dotted line), tight junctions are intact which restricts the leakage of paracellular, typically small hydrophilic, compounds, across the barrier and into the brain.
T831 8425-8624 Sentence denotes Additionally, there is a basal expression of efflux transporters, such as P-glycoprotein (P-gp), which effluxes substrates out of the brain, serving to restrict overall accumulation within the brain.
T832 8625-8819 Sentence denotes In the setting of HIV and opiate exposure (represented below the dotted line), there is a breakdown of the tight junction proteins and increased leakage of paracellular compounds into the brain.
T833 8820-9141 Sentence denotes Additionally, opiate exposure increases efflux transporter expression, including P-gp and potentially breast cancer resistance protein (Bcrp), thereby restricting overall brain penetration of drugs (like many antiretroviral drugs) which are substrates for these transporters and in response to HIV and/or opioid exposure.
T834 9143-9182 Sentence denotes White Matter/Oligodendroglial Pathology
T835 9183-9234 Sentence denotes HIV can cause white matter damage (Gosztonyi et al.
T836 9235-9256 Sentence denotes 1994; Langford et al.
T837 9257-9274 Sentence denotes 2002; Xuan et al.
T838 9275-9329 Sentence denotes 2013) even with less severe forms of HAND (Chen et al.
T839 9330-9348 Sentence denotes 2009; Leite et al.
T840 9349-9368 Sentence denotes 2013; Correa et al.
T841 9369-9375 Sentence denotes 2015).
T842 9376-9486 Sentence denotes Diffusion tensor magnetic resonance imaging (DTI) demonstrates white matter damage early in HAND (Ragin et al.
T843 9487-9512 Sentence denotes 2004; Stubbe-Drger et al.
T844 9513-9531 Sentence denotes 2012; Leite et al.
T845 9532-9551 Sentence denotes 2013; Correa et al.
T846 9552-9558 Sentence denotes 2015).
T847 9559-9667 Sentence denotes White matter deficits are associated with cognitive impairment, including shortfalls in memory (Ragin et al.
T848 9668-9708 Sentence denotes 2005), executive function (Correa et al.
T849 9709-9738 Sentence denotes 2015), motor speed (Wu et al.
T850 9739-9764 Sentence denotes 2006; Stubbe-Drger et al.
T851 9765-9825 Sentence denotes 2012), and perhaps depression (Schmaal and van Velzen 2019).
T852 9826-9928 Sentence denotes Preclinical studies in simian immunodeficiency virus- (SIV-) infected rhesus macaques (Marcario et al.
T853 9929-9980 Sentence denotes 2008) and HIV-infected humanized mice (Boska et al.
T854 9981-10017 Sentence denotes 2014) support the clinical findings.
T855 10018-10110 Sentence denotes Injury to oligodendrocytes (OLs) can occur very early in the disease (see review, Liu et al.
T856 10111-10118 Sentence denotes 2016b).
T857 10119-10230 Sentence denotes Viral proteins, including Tat, gp120, and Nef, have been implicated in OL injury in vitro (Kimura-Kuroda et al.
T858 10231-10252 Sentence denotes 1994; Bernardo et al.
T859 10253-10271 Sentence denotes 1997; Radja et al.
T860 10272-10293 Sentence denotes 2003; Nukuzuma et al.
T861 10294-10310 Sentence denotes 2012; Zou et al.
T862 10311-10360 Sentence denotes 2015), and in animal models in vivo (Radja et al.
T863 10361-10380 Sentence denotes 2003; Hauser et al.
T864 10381-10397 Sentence denotes 2009; Zou et al.
T865 10398-10404 Sentence denotes 2015).
T866 10405-10495 Sentence denotes Importantly, Tat has been detected in OLs in the brains of AIDS patients (Del Valle et al.
T867 10496-10502 Sentence denotes 2000).
T868 10503-10567 Sentence denotes HIV likely damages OLs through both direct and indirect actions.
T869 10568-10643 Sentence denotes OLs lack CD4, and reports of OL infection by HIV are variable (Esiri et al.
T870 10644-10665 Sentence denotes 1991; Albright et al.
T871 10666-10692 Sentence denotes 1996; Wohlschlaeger et al.
T872 10693-10801 Sentence denotes 2009); thus, HIV infection of OLs is unlikely a major avenue of OL or white matter damage (discussed below).
T873 10802-10989 Sentence denotes Alternatively, bystander damage to OLs through the production of “virotoxins” and “cellular toxins” (Nath 1999) by infected neighboring cells is more likely to be operative (Hauser et al.
T874 10990-11006 Sentence denotes 2009; Zou et al.
T875 11007-11026 Sentence denotes 2015; Jensen et al.
T876 11027-11043 Sentence denotes 2019; Zou et al.
T877 11044-11050 Sentence denotes 2019).
T878 11051-11105 Sentence denotes ARVs also contribute to OL cytotoxicity (Jensen et al.
T879 11106-11124 Sentence denotes 2015; Festa et al.
T880 11125-11144 Sentence denotes 2019; Jensen et al.
T881 11145-11151 Sentence denotes 2019).
T882 11152-11343 Sentence denotes HIV-1 Tat directly induces damage in isolated OLs through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartic acid (NMDA) receptor-dependent mechanisms (Zou et al.
T883 11344-11413 Sentence denotes 2015) and is also associated with abnormal Kv1.3 activity (Liu et al.
T884 11414-11420 Sentence denotes 2017).
T885 11421-11517 Sentence denotes Immature OLs are preferentially targeted by Tat compared to differentiated OLs (Khurdayan et al.
T886 11518-11535 Sentence denotes 2004; Hahn et al.
T887 11536-11552 Sentence denotes 2012; Zou et al.
T888 11553-11565 Sentence denotes 2015, 2019).
T889 11566-11814 Sentence denotes While the reasons why immature OLs are more susceptible to Tat are unclear, unlike mature OLs, Tat preferentially upregulates GSK-3β signaling in undifferentiated OLs by inhibiting Ca2+/calmodulin-dependent protein kinase II β (CaMKIIβ) (Zou et al.
T890 11815-11821 Sentence denotes 2019).
T891 11822-11986 Sentence denotes Opioid abuse by itself can result in demyelination, leukoencephalopathy, and lesions in white matter (Offiah and Hall 2008; Eran and Barak 2009; Morales Odia et al.
T892 11987-12004 Sentence denotes 2010; Bora et al.
T893 12005-12020 Sentence denotes 2012; Li et al.
T894 12021-12127 Sentence denotes 2013), and the degree of myelin disruption correlates with the duration of opiate dependence (Ivers et al.
T895 12128-12134 Sentence denotes 2018).
T896 12135-12352 Sentence denotes Chronic oxycodone exposure in rats causes some axonopathies and reduces the size of axonal fascicles, decreases myelin basic protein levels, and causes the accumulation of amyloid-β precursor protein (APP) (Fan et al.
T897 12353-12359 Sentence denotes 2018).
T898 12360-12515 Sentence denotes Most preclinical studies have examined the effects of opioids and opioid receptor blockade on OL maturation and/or the timing of myelination (Hauser et al.
T899 12516-12534 Sentence denotes 1993; Knapp et al.
T900 12535-12561 Sentence denotes 1998; Stiene-Martin et al.
T901 12562-12582 Sentence denotes 2001; Sanchez et al.
T902 12583-12601 Sentence denotes 2008; Knapp et al.
T903 12602-12629 Sentence denotes 2009; Vestal-Laborde et al.
T904 12630-12636 Sentence denotes 2014).
T905 12637-12715 Sentence denotes OLs can transiently express MORs and other opioid receptor types (Knapp et al.
T906 12716-12740 Sentence denotes 1998; Tryoen-Toth et al.
T907 12741-12759 Sentence denotes 2000; Knapp et al.
T908 12760-12786 Sentence denotes 2001; Stiene-Martin et al.
T909 12787-12793 Sentence denotes 2001).
T910 12794-12921 Sentence denotes Selective MOR and possibly KOR activation can directly modulate the growth of OLs in vitro (Knapp and Hauser 1996; Knapp et al.
T911 12922-12934 Sentence denotes 1998, 2001).
T912 12935-13054 Sentence denotes Despite long-standing evidence of white matter damage early during the infection even in asymptomatic PWH (Price et al.
T913 13055-13072 Sentence denotes 1988; Gray et al.
T914 13073-13090 Sentence denotes 1996; Chen et al.
T915 13091-13116 Sentence denotes 2009; Stubbe-Drger et al.
T916 13117-13136 Sentence denotes 2012; Jensen et al.
T917 13137-13242 Sentence denotes 2019), few studies have examined how opiate exposure affects OLs and myelin in neuroHIV (Tables 1 and 2).
T918 13243-13388 Sentence denotes Increased demyelination is reported in SIV-infected rhesus macaques chronically treated with morphine (4× daily, up to 59 weeks) (Marcario et al.
T919 13389-13395 Sentence denotes 2008).
T920 13396-13568 Sentence denotes Specifically, morphine-treated SIV macaques developed more subtle, focal, dysmyelinating lesions, with accumulations of macrophages in areas of myelin loss (Marcario et al.
T921 13569-13624 Sentence denotes 2008), as well as accompanying gliosis (Marcario et al.
T922 13625-13650 Sentence denotes 2008; Rivera-Amill et al.
T923 13651-13672 Sentence denotes 2010a; Bokhari et al.
T924 13673-13679 Sentence denotes 2011).
T925 13680-13899 Sentence denotes Morphine exposure increased degeneration of OLs in Tat+ mice, which was accompanied by elevations in caspase-3 activation and TUNEL reactivity in OLs and reversible by naloxone or naltrexone, respectively (Hauser et al.
T926 13900-13906 Sentence denotes 2009).
T927 13907-13970 Sentence denotes Although OLs can express MOR both in vivo (Stiene-Martin et al.
T928 13971-14004 Sentence denotes 2001) and in vitro (Hauser et al.
T929 14005-14108 Sentence denotes 2009), it remains unclear the extent to which MOR activation in OLs directly mediates HIV pathogenesis.
T930 14110-14171 Sentence denotes Neural Progenitors as an HIV Reservoir and Target for Opioids
T931 14172-14246 Sentence denotes Even though neural progenitors (Krathwohl and Kaiser 2004; Lawrence et al.
T932 14247-14272 Sentence denotes 2004; Rothenaigner et al.
T933 14273-14294 Sentence denotes 2007; Schwartz et al.
T934 14295-14316 Sentence denotes 2007; Balinang et al.
T935 14317-14360 Sentence denotes 2017), neuroblast cell lines (Ensoli et al.
T936 14361-14386 Sentence denotes 1994; Rothenaigner et al.
T937 14387-14434 Sentence denotes 2007), and/or immature astroglia (Atwood et al.
T938 14435-14457 Sentence denotes 1993; Tornatore et al.
T939 14458-14476 Sentence denotes 1994; Barat et al.
T940 14477-14560 Sentence denotes 2018) can harbor HIV infection (reviewed by Hauser and Knapp 2014; Putatunda et al.
T941 14561-14679 Sentence denotes 2019), the degree to which they are a source of active infection or serve as a latent viral reservoir (Blankson et al.
T942 14680-14699 Sentence denotes 2002; Bruner et al.
T943 14700-14788 Sentence denotes 2019) by retaining intact proviral DNA within incipient macroglial progeny is uncertain.
T944 14789-14865 Sentence denotes In fact, spurious reports of HIV-infected adult neurons (Torres-Munoz et al.
T945 14866-14891 Sentence denotes 2001; Canto-Nogues et al.
T946 14892-15049 Sentence denotes 2005) may result from the retention of proviral genes that integrated into pluripotent neural progenitors or neuroblasts at earlier stages during maturation.
T947 15050-15169 Sentence denotes Importantly, prolonged exposure to opioids can increase the production of HIV in human neural progenitor cells (hNPCs).
T948 15170-15335 Sentence denotes Exposure of R5-tropic HIVBaL-infected hNPCs to morphine continuously for 21 d increased viral production compared to HIVBaL infection alone in vitro (Balinang et al.
T949 15336-15342 Sentence denotes 2017).
T950 15343-15450 Sentence denotes Besides being able to infect hNPCs, HIV may also affect their maturation and the fate of neural stem cells.
T951 15451-15515 Sentence denotes That HIV or gp120 can inhibit adult neurogenesis (Okamoto et al.
T952 15516-15532 Sentence denotes 2007; Lee et al.
T953 15533-15555 Sentence denotes 2013; Putatunda et al.
T954 15556-15640 Sentence denotes 2018) has been the topic of past reviews (Schwartz and Major 2006; Venkatesan et al.
T955 15641-15658 Sentence denotes 2007; Peng et al.
T956 15659-15735 Sentence denotes 2008, 2011; Ferrell and Giunta 2014; Hauser and Knapp 2014; Putatunda et al.
T957 15736-15742 Sentence denotes 2019).
T958 15743-15950 Sentence denotes How HIV inhibits the self-renewal, tripotential differentiation, and survival of neural progenitors/stem cells or the genesis of adult neurons in the subgranular zone (SGZ) of the dentate gyrus is uncertain.
T959 15951-16128 Sentence denotes HIV and gp120 [via actions at the same chemokine receptor(s) (Tran and Miller 2005; Li and Ransohoff 2008)] are proposed to modulate the adult neurogenesis via Notch (Fan et al.
T960 16129-16254 Sentence denotes 2016), by obstructing a cell cycle checkpoint via the activation MAPK-activated protein kinase 2 and Cdc25B/C (Okamoto et al.
T961 16255-16332 Sentence denotes 2007), or through signaling by platelet-derived growth factor BB (Chao et al.
T962 16333-16358 Sentence denotes 2014) or BDNF (Lee et al.
T963 16359-16365 Sentence denotes 2013).
T964 16366-16655 Sentence denotes The extent that HIV regulates the genesis of neural progenitors within the subventricular zone of the developing CNS through similar mechanisms as in the adult SGZ of the dentate gyrus is uncertain—even though HIV disrupts the generation of neurons and glia during maturation or in adults.
T965 16656-16825 Sentence denotes For example, MAPK/ERK1/2 enhances p53- and p21-dependent downregulation of cyclin D1 hindering progression through the G1 phase of the cell cycle in hNPCs (Mishra et al.
T966 16826-16844 Sentence denotes 2010; Malik et al.
T967 16845-16851 Sentence denotes 2014).
T968 16852-17024 Sentence denotes Importantly, opioids too can affect the genesis of neurons and glia during maturation or in the adult directly via convergent pathways (Hauser and Knapp 2018; Kibaly et al.
T969 17025-17153 Sentence denotes 2018) suggesting yet another site of opioid and HIV interactions in dysregulating the creation and fate of new neurons and glia.
T970 17154-17251 Sentence denotes Few studies have examined the interplay between opioids, neural progenitors and HIV/HIV proteins.
T971 17252-17485 Sentence denotes Sustained exposure (4 d) to morphine (500 nM) and Tat1–72 (100 nM) decreased the viability of MOR-expressing striatal glial precursors, and to a lesser extent astrocytes, and this coincided with caspase-3 activation (Khurdayan et al.
T972 17486-17492 Sentence denotes 2004).
T973 17493-17707 Sentence denotes By contrast, comparably administered morphine or Tat alone was sufficient to decrease the viability of immature glia/glial progenitors in spinal cord cultures, while Tat and morphine failed to interact (Buch et al.
T974 17708-17714 Sentence denotes 2007).
T975 17715-17944 Sentence denotes Collectively, these findings were the first to indicate that opioid and/or Tat could enhance programmed cell death in subpopulations of glial precursors in a developmentally regulated and region-dependent manner (Khurdayan et al.
T976 17945-17962 Sentence denotes 2004; Buch et al.
T977 17963-17969 Sentence denotes 2007).
T978 17970-18263 Sentence denotes In human glial progenitors, co-administering morphine (500 nM) increased the antiproliferative effects of Tat (12–48 h) or conditioned medium from HIV-1SF162-infected MDMs (12 h), while paradoxically reversing the antiproliferative effects from HIV-1IIIB conditioned medium (12 h) (Hahn et al.
T979 18264-18270 Sentence denotes 2012).
T980 18271-18479 Sentence denotes In these studies, Tat or HIV exposure reduced the proliferation of Sox2+ and Olig2+ undifferentiated glial and oligodendroglial progenitors, respectively, while progenitor viability was unchanged (Hahn et al.
T981 18480-18486 Sentence denotes 2012).
T982 18487-18758 Sentence denotes In human neural progenitor cells (hNPCs), sustained infection with R5-tropic HIVBaL increased the proliferation and premature differentiation of hNPCs into both neurons and astrocytes, and both measures were significantly enhanced by morphine co-exposure (Balinang et al.
T983 18759-18765 Sentence denotes 2017).
T984 18766-18821 Sentence denotes Importantly, immunoneutralizing antibodies (Hahn et al.
T985 18822-18883 Sentence denotes 2012) or the selective antagonist, maraviroc (Balinang et al.
T986 18884-19057 Sentence denotes 2017), were able to significantly attenuate the consequences of R5-tropic HIV infection on hNPC differentiation and fate confirming a direct role of CCR5 in these processes.
T987 19058-19226 Sentence denotes Lastly, decreases in the proliferation of hNPCs seen with morphine and Tat are, in part, regulated by ERK1/2-dependent increases in p53 and p21 expression (Malik et al.
T988 19227-19319 Sentence denotes 2014) and can be modulated by PDGF BB suggesting a possible therapeutic target (Malik et al.
T989 19320-19326 Sentence denotes 2011).
T990 19327-19521 Sentence denotes Thus, morphine can exaggerate R5-tropic HIV-induced alterations in the maturation and fate of human and rodent NPCs, thereby further disrupting the balance of neural cell types and CNS function.