Effects of HIV-1 viral protein Tat on the viability and function of oligodendroglial cells

Myelin pallor is frequently reported in HIV patients, and can occur in the CNS prior to other evidence of disease process. Our exploratory studies showed that oligodendrocytes (OLs) are direct targets of HIV-1 Tat (transactivator of transcription). Tat induces a dose-dependent increase of intracellular Ca2+ level ([Ca2+]i) in cultured murine OLs, which can be attenuated by ionotropic glutamate receptor (iGluR) antagonists MK801 and CNQX. The Tat-induced [Ca2+]i increase leads to increased death in immature (O4+, MBP-), but not mature (O4+, MBP+) OLs, over 96 h. In addition, Tat-induced [Ca2+]i increase also reduced myelin-like membrane production by mature OLs. Calcium/Calmodulin dependent kinase IIβ (CaMKIIβ) and glycogen synthase kinase 3β (GSK3β) have been known to regulate differentiation, myelination, and apoptosis in OLs. Since both CaMKIIβ and GSK3β are important downstream modulators of [Ca2+]i change, we hypothesized that the detrimental effects of Tat on immature/mature OL viability and function are mediated via CaMKIIβ and GSK3β activation. Our results showed that Tat activates both CaMKIIβ and GSK3β in immature OLs, but only activates CaMKIIβ in mature OLs. MK801 completely blocks Tat-induced CaMKIIβ and GSK3β activation in both immature and mature OLs, while CNQX blocks GSK3β activation, but has only a partial effect on CaMKIIβ activity. Blocking iGluRs or inhibiting GSK3β both rescue Tat-induced immature OL death, but only MK801 reverses the membrane injury in mature OLs. Together, these data strongly suggest that 1) activity of CaMKIIβ and GSK3β in OLs can be regulated by Tat-induced iGluRs activation and 2) OLs at different developmental stages show different responses to Tat, possibly due to activation of different signaling pathways

Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia

<p>Abstract</p> <p>Background</p> <p>Several classes of histone deacetylases (HDACs) are expressed in the spinal cord that is a critical structure of the nociceptive pathway. HDAC-regulated histone acetylation is an important component of chromatin remodeling leading to epigenetic regulation of gene transcription. To understand the role of histone acetylation in epigenetic regulation of pathological pain, we have studied the impact of different classes of HDACs in the spinal cord on inflammatory hyperalgesia induced by complete Freund's adjuvant (CFA).</p> <p>Results</p> <p>We intrathecally applied inhibitors specific to different classes of HDACs and evaluated their impact on inflammatory hyperalgesia. Pre-injected inhibitors targeting class I as well as II (SAHA, TSA, LAQ824) or IIa (VPA, 4-PB) HDACs significantly delayed the thermal hyperalgesia induced by unilateral CFA injection in the hindpaw. Existing hyperalgesia induced by CFA was also attenuated by the HDAC inhibitors (HDACIs). In contrast, these inhibitors did not interfere with the thermal response either in naïve animals, or on the contralateral side of inflamed animals. Interestingly, MS-275 that specifically inhibits class I HDACs failed to alter the hyperalgesia although it increased histone 3 acetylation in the spinal cord as SAHA did. Using immunoblot analysis, we further found that the levels of class IIa HDAC members (HDAC4, 5, 7, 9) in the spinal dorsal horn were upregulated following CFA injection while those of class I HDAC members (HDAC1, 2, 3) remained stable or were slightly reduced.</p> <p>Conclusions</p> <p>Our data suggest that activity of class II HDACs in the spinal cord is critical to the induction and maintenance of inflammatory hyperalgesia induced by CFA, while activity of class I HDACs may be unnecessary. Comparison of the effects of HDACIs specific to class II and IIa as well as the expression pattern of different HDACs in the spinal cord in response to CFA suggests that the members of class IIa HDACs may be potential targets for attenuating persistent inflammatory pain.</p

Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

<p>Abstract</p> <p>Background</p> <p>Fractalkine/CX₃CL1 and its cognate receptor CX₃CR1 are abundantly expressed in the CNS. Fractalkine is an unusual C-X3-C motif chemokine that is important in neuron-microglial communication, a co-receptor for HIV infection, and can be neuroprotective. To assess the effects of fractalkine on opiate-HIV interactive neurotoxicity, wild-type murine striatal neurons were co-cultured with mixed glia from the striata of wild-type or <it>Cx3cr1 </it>knockout mice ± HIV-1 Tat and/or morphine. Time-lapse digital images were continuously recorded at 20 min intervals for up to 72 h using computer-aided microscopy to track the same cells repeatedly.</p> <p>Results</p> <p>Co-exposure to Tat and morphine caused synergistic increases in neuron death, dendritic pruning, and microglial motility as previously reported. Exogenous fractalkine prevented synergistic Tat and morphine-induced dendritic losses and neuron death even though the inflammatory mediator TNF-α remained significantly elevated. Antibody blockade of CX₃CR1 mimicked the toxic effects of morphine plus Tat, but did not add to their toxicity; while fractalkine failed to protect wild-type neurons co-cultured with <it>Cx₃cr1</it>^-/--null glia against morphine and Tat toxicity. Exogenous fractalkine also normalized microglial motility, which is elevated by Tat and morphine co-exposure, presumably limiting microglial surveillance that may lead to toxic effects on neurons. Fractalkine immunofluorescence was expressed in neurons and to a lesser extent by other cell types, whereas CX₃CR1 immunoreactivity or GFP fluorescence in cells cultured from the striatum of <it>Cx3cr1</it>^-/-(<it>Cx3cr1</it>^GFP/GFP) mice were associated with microglia. Immunoblotting shows that fractalkine levels were unchanged following Tat and/or morphine exposure and there was no increase in released fractalkine as determined by ELISA. By contrast, CX₃CR1 protein levels were markedly downregulated.</p> <p>Conclusions</p> <p>The results suggest that deficits in fractalkine-CX₃CR1 signaling contribute to the synergistic neurotoxic effects of opioids and Tat. Importantly, exogenous fractalkine can selectively protect neurons from the injurious effects of chronic opioid-HIV-1 Tat co-exposure, and this suggests a potential therapeutic course for neuroAIDS. Although the cellular mechanisms underlying neuroprotection are not certain, findings that exogenous fractalkine reduces microglial motility and fails to protect neurons co-cultured with <it>Cx3cr1</it>^-/-mixed glia suggest that fractalkine may act by interfering with toxic microglial-neuron interactions.</p

Global Infectious Diseases in August of 2022: Monthly Analysis

Infectious diseases have greatly affected the development of human history, owing to their unpredictable zoonotic characteristics. The recording of infectious diseases epidemic data provides information on disease transmission trends, and enables research on the risk of penitential epidemics and the mechanisms of transmission of infectious diseases. Recent years have seen a significant increase in the number of confirmed and fatal cases of COVID-19 since it became a pandemic in late 2019. Monkeypox also has potential for global transmission, because the World Health Organization (WHO) [ 1 ] reported cases of MPXV in at least 12 Countries that are not endemic for monkeypox virus. Africa and Southeast Asia appear to be the main regions where mosquito-borne diseases are epidemic, possibly because of the rainy weather in these regions in the past month. Tracking disease incidence and epidemic tendency remains imperative in these areas, although most infectious diseases appear to be dispersed and transmitted in only several areas at the moment

Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors

<p>Abstract</p> <p>Background</p> <p>In addition to caudal subnucleus caudalis (Vc) of the spinal trigeminal complex, recent studies indicate that the subnuclei interpolaris/caudalis (Vi/Vc) transition zone plays a unique role in processing deep orofacial nociceptive input. Studies also suggest that glia and inflammatory cytokines contribute to the development of persistent pain. By systematically comparing the effects of microinjection of the antiinflammatory cytokine interleukin (IL)-10 and two glial inhibitors, fluorocitrate and minocycline, we tested the hypothesis that there was a differential involvement of Vi/Vc and caudal Vc structures in deep and cutaneous orofacial pain.</p> <p>Results</p> <p>Deep or cutaneous inflammatory hyperalgesia, assessed with von Frey filaments, was induced in rats by injecting complete Freund's adjuvant (CFA) into the masseter muscle or skin overlying the masseter, respectively. A unilateral injection of CFA into the masseter or skin induced ipsilateral hyperalgesia that started at 30 min, peaked at 1 d and lasted for 1-2 weeks. Secondary hyperalgesia on the contralateral site also developed in masseter-, but not skin-inflamed rats. Focal microinjection of IL-10 (0.006-1 ng), fluorocitrate (1 μg), and minocycline (0.1-1 μg) into the ventral Vi/Vc significantly attenuated masseter hyperalgesia bilaterally but without an effect on hyperalgesia after cutaneous inflammation. Injection of the same doses of these agents into the caudal Vc attenuated ipsilateral hyperalgesia after masseter and skin inflammation, but had no effect on contralateral hyperalgesia after masseter inflammation. Injection of CFA into the masseter produced significant increases in N-methyl-D-aspartate (NMDA) receptor NR1 serine 896 phosphorylation and glial fibrillary acidic protein (GFAP) levels, a marker of reactive astrocytes, in Vi/Vc and caudal Vc. In contrast, cutaneous inflammation only produced similar increases in the Vc.</p> <p>Conclusion</p> <p>These results support the hypothesis that the Vi/Vc transition zone is involved in deep orofacial injury and suggest that glial inhibition and interruption of the cytokine cascade after inflammation may provide pain relief.</p

Global Infectious Diseases in September 2022: Monthly Analysis

The threat of infectious diseases caused by pathogenic microorganisms to both human health and the economy is enormous. Coronavirus Disease 2019 (COVID-19) remains a global pandemic. In contrast to many other infectious diseases, monkeypox spreads rapidly and cannot be ignored. Collection of data on contagious diseases can provide quantitative evidence to support effective pandemic control strategies. Global data on predominant infectious diseases collected in the past several weeks and a summary of their epidemiology are presented herein

Global Infectious Diseases in October 2022: Monthly Analysis

Infectious diseases continue to pose a major threat to worldwide public health. Infections by Coronavirus Disease 2019 have eased but continue to negatively affect international economic development. The situation of other infectious diseases, such as monkeypox and mosquito-borne diseases, became stable in October. Monitoring epidemic situation of infectious diseases can provide rapid insight into global transmission trends and assist in predicting epidemic situations. Visualizations and analyses summarizing the past few weeks of global data on major infectious diseases are provided

Global Infectious Diseases in December 2022: Monthly Analysis

The emergence and reoccurrence of infectious diseases constitute a significant threat to human health. Data for this paper were mainly obtained from official websites, such as the WHO and national CDC websites. The report summarizes and analyzes information on infectious diseases for early outbreak monitoring from 24 November to 23 December 2022. Monkeypox cases declined in December 2022 with few deaths, while cholera infections have increased in African regions and war-torn countries. Most sub-Saharan countries are affected by insect-borne diseases, such as dengue, Lassa, and chikungunya fever

Global Infectious Diseases in February 2023: Monthly Analysis

Public health security in human societies is placed under enormous strain by infectious disease epidemics. According to the WHO, COVID-19 and Mpox remain on the list of PHEICs, whereas cholera, dengue, and other contagious diseases remain endemic in several countries and regions. Data on prevalent infectious diseases have been collected worldwide in recent weeks, and may provide new ideas for international collaboration in public health

Global Infectious Diseases in June 2023: Monthly Analysis

Infectious diseases are a class of diseases caused by various pathogens that can be transmitted between humans and animals or between humans and animals, thus seriously affecting the development of human society. To control the spread of infectious diseases worldwide and ensure the safety of people’s lives, it is essential to regularly analyze global infectious disease cases. This review is based on data from the World Health Organization, the Centers for Disease Control in countries around the world, Outbreak News Today and many other epidemiological websites to predict the global infectious disease outbreak trend. In addition, using the Shuci Technology global epidemic information monitoring system, we analyzed the distribution of infectious diseases that occurred around the world from 24 May 2023 to 23 June 2023